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1.
Am J Hum Genet ; 107(1): 164-172, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32553196

RESUMO

CNOT1 is a member of the CCR4-NOT complex, which is a master regulator, orchestrating gene expression, RNA deadenylation, and protein ubiquitination. We report on 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. To link CNOT1 dysfunction to the neurodevelopmental phenotype observed, we generated variant-specific Drosophila models, which showed learning and memory defects upon CNOT1 knockdown. Introduction of human wild-type CNOT1 was able to rescue this phenotype, whereas mutants could not or only partially, supporting our hypothesis that CNOT1 impairment results in neurodevelopmental delay. Furthermore, the genetic interaction with autism-spectrum genes, such as ASH1L, DYRK1A, MED13, and SHANK3, was impaired in our Drosophila models. Molecular characterization of CNOT1 variants revealed normal CNOT1 expression levels, with both mutant and wild-type alleles expressed at similar levels. Analysis of protein-protein interactions with other members indicated that the CCR4-NOT complex remained intact. An integrated omics approach of patient-derived genomics and transcriptomics data suggested only minimal effects on endonucleolytic nonsense-mediated mRNA decay components, suggesting that de novo CNOT1 variants are likely haploinsufficient hypomorph or neomorph, rather than dominant negative. In summary, we provide strong evidence that de novo CNOT1 variants cause neurodevelopmental delay with a wide range of additional co-morbidities. Whereas the underlying pathophysiological mechanism warrants further analysis, our data demonstrate an essential and central role of the CCR4-NOT complex in human brain development.


Assuntos
Deficiências do Desenvolvimento/genética , Expressão Gênica/genética , Transtornos do Neurodesenvolvimento/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , RNA/genética , Receptores CCR4/genética , Fatores de Transcrição/genética , Alelos , Feminino , Variação Genética/genética , Haploinsuficiência/genética , Heterozigoto , Humanos , Masculino , Malformações do Sistema Nervoso/genética , Fenótipo , Estabilidade Proteica
2.
World Neurosurg ; 138: 461-467, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32200015

RESUMO

Caudal regression syndrome (CRS) represents a spectrum of clinical phenotypes with varying degrees of malformation of the lower body with involvement of structures deriving from all 3 layers of the trilaminar embryo. We review areas of active investigation in the diagnosis, etiology, epidemiology, and treatment of the disease with a focus on underlying genetics. CRS pathobiology is complex and multifactorial with a significant contribution from environmental factors as evidenced in twin studies. Contemporary genomic and genetic investigations in both human primary tissue and murine in vitro and in vivo models implicate various genes associated with caudal differentiation and neural cell migration in embryogenesis. A large number of identified targets center around the metabolic regulation of retinoic acid and its derivatives. Dysregulation of retinoic acid homeostasis has been associated with abnormal embryonic cell migration, differentiation, and organogenesis with resulting malformations and agenesis in both a laboratory and a clinical setting. There appears to be a significant overlap in potential genetic targets with CRS and other developmental syndromes with similar presentations, such as VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) association. CRS represents a spectrum of caudal developmental abnormalities with treatment options limited to mild and moderate expressions of disease. Continued research is necessary to further clarify mechanisms of disease pathobiology and complex polygenetic and environmental interaction. Despite this, progress has been made in identifying genetic targets and downstream effectors contributing to preclinical and clinical progression.


Assuntos
Anormalidades Múltiplas/genética , Genômica , Deformidades Congênitas dos Membros/genética , Malformações do Sistema Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Animais , Humanos , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/patologia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Tretinoína/metabolismo
3.
Am J Hum Genet ; 106(4): 570-583, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197074

RESUMO

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.


Assuntos
Deficiências do Desenvolvimento/genética , Variação Genética/genética , Leucoencefalopatias/genética , Malformações do Sistema Nervoso/genética , eIF-2 Quinase/genética , Adolescente , Ataxia/genética , Criança , Pré-Escolar , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Humanos , Lactente , Masculino , Substância Branca/patologia
4.
Am J Hum Genet ; 106(4): 484-495, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32220290

RESUMO

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.


Assuntos
Aciltransferases/genética , Moléculas de Adesão Celular/genética , Doenças Cerebelares/genética , Epilepsia/genética , Variação Genética/genética , Hipotonia Muscular/genética , Transtornos do Neurodesenvolvimento/genética , Anormalidades Múltiplas/genética , Alelos , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Malformações do Sistema Nervoso/genética , Linhagem , Síndrome
5.
Eur J Paediatr Neurol ; 26: 46-60, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32169460

RESUMO

OBJECTIVE: To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome. METHODS: We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses. RESULTS: The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal. CONCLUSIONS: TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 - associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.


Assuntos
Feto/anormalidades , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Tubulina (Proteína)/genética , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Masculino , Mutação , Gravidez , Síndrome
6.
BMC Neurol ; 20(1): 58, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061250

RESUMO

BACKGROUND: Primary microcephaly is defined as reduced occipital-frontal circumference noticeable before 36 weeks of gestation. Large amount of insults might lead to microcephaly including infections, hypoxia and genetic mutations. More than 16 genes are described in autosomal recessive primary microcephaly. However, the cause of microcephaly remains unclear in many cases after extensive investigations and genetic screening. CASE PRESENTATION: Here, we described the case of a boy with primary microcephaly who presented to a neurology clinic with short stature, global development delay, dyskinetic movement, strabismus and dysmorphic features. We performed microcephaly investigations and genetic panels. Then, we performed whole-exome sequencing to identify any genetic cause. Microcephaly investigations and genetic panels were negative, but we found a new D317V homozygous mutation in TELOE-2 interacting protein 2 (TTI2) gene by whole-exome sequencing. TTI2 is implicated in DNA damage response and mutation in that gene was previously described in mental retardation, autosomal recessive 39. CONCLUSIONS: We described the first French Canadian case with primary microcephaly and global developmental delay secondary to a new D317V homozygous mutation in TTI2 gene. Our report also highlights the importance of TTI2 protein in brain development.


Assuntos
Microcefalia/genética , Malformações do Sistema Nervoso/genética , Sequenciamento Completo do Exoma , Canadá , Pré-Escolar , Testes Genéticos , Homozigoto , Humanos , Lactente , Masculino , Mutação
7.
Eur J Paediatr Neurol ; 25: 106-112, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32014392

RESUMO

OBJECTIVES: To systematically investigate chromosomal abnormalities and copy number variants (CNVs) in fetuses with different types of ventriculomegaly (VM) by karyotyping and/or chromosomal microarray analysis (CMA). METHODS: This retrospective study included 312 fetuses diagnosed with VM. Amniotic fluid and umbilical blood samples were collected by amniocentesis and cordocentesis, respectively, and subjected to karyotyping and/or CMA. Subgroup analysis by VM type, including mild VM (MVM) and severe VM (SVM), unilateral and bilateral VM, isolated VM (IVM), and non-isolated VM (NIVM), was performed. RESULTS: The detection rate of chromosomal abnormalities was 12.1% (34/281) by karyotyping and 20.6% when CMA was additionally performed (P < 0.05). Abnormalities were identified by CMA in 17.4% (38/218) of fetuses and pathogenic CNVs in 5.0% (11/218). Notably, CMA detected CNVs in 10.6% (23/218) of fetuses with normal karyotypes. The incidence of chromosomal abnormalities by karyotyping was higher in bilateral than in unilateral VM (20.5% versus 6.5%), whereas the incidence detected by CMA was higher in NIVM than in IVM (21.4% versus 10.3%; both P < 0.05). In NIVM, CMA provided an additional detection rate of 11.4% (16/140) and a detection rate of 10.0% for pathogenic CNVs and aneuploidies. Central nervous system (CNS) abnormalities were the most common other ultrasonic abnormalities. CONCLUSIONS: CMA is highly recommended for prenatal diagnosis of fetal VM together with karyotyping, especially in fetuses with bilateral VM and NIVM with abnormal CNS findings. Further study is necessary to explore the relationships between genotypes and phenotypes to facilitate prenatal diagnosis of fetal VM.


Assuntos
Ventrículos Cerebrais/anormalidades , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Diagnóstico Pré-Natal/métodos , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Feminino , Feto/anormalidades , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/etiologia , Cariotipagem/métodos , Malformações do Sistema Nervoso/complicações , Gravidez , Estudos Retrospectivos
8.
FASEB J ; 34(1): 631-647, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914608

RESUMO

In mammalian cells, the catabolic activity of the dNTP triphosphohydrolase SAMHD1 sets the balance and concentration of the four dNTPs. Deficiency of SAMHD1 leads to unequally increased pools and marked dNTP imbalance. Imbalanced dNTP pools increase mutation frequency in cancer cells, but it is not known if the SAMHD1-induced dNTP imbalance favors accumulation of somatic mutations in non-transformed cells. Here, we have investigated how fibroblasts from Aicardi-Goutières Syndrome (AGS) patients with mutated SAMHD1 react to the constitutive pool imbalance characterized by a huge dGTP pool. We focused on the effects on dNTP pools, cell cycle progression, dynamics and fidelity of DNA replication, and efficiency of UV-induced DNA repair. AGS fibroblasts entered senescence prematurely or upregulated genes involved in G1/S transition and DNA replication. The normally growing AGS cells exhibited unchanged DNA replication dynamics and, when quiescent, faster rate of excision repair of UV-induced DNA damages. To investigate whether the lack of SAMHD1 affects DNA replication fidelity, we compared de novo mutations in AGS and WT cells by exome next-generation sequencing. Somatic variant analysis indicated a mutator phenotype suggesting that SAMHD1 is a caretaker gene whose deficiency is per se mutagenic, promoting genome instability in non-transformed cells.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , Fibroblastos/metabolismo , Mutação/genética , Malformações do Sistema Nervoso/genética , Proteína 1 com Domínio SAM e Domínio HD/deficiência , Dano ao DNA/genética , Replicação do DNA/genética , Humanos , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteína 1 com Domínio SAM e Domínio HD/genética
9.
Cell Mol Life Sci ; 77(15): 2931-2948, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31996954

RESUMO

Our body expresses sensors to detect pathogens through the recognition of expressed molecules, including nucleic acids, lipids, and proteins, while immune tolerance prevents an overreaction with self and the development of autoimmune disease. Adenosine (A)-to-inosine (I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a post-transcriptional modification that can potentially occur at over 100 million sites in the human genome, mainly in Alu repetitive elements that preferentially form a double-stranded RNA (dsRNA) structure. A-to-I conversion within dsRNA, which may induce a structural change, is required to escape from the host immune system, given that endogenous dsRNAs transcribed from Alu repetitive elements are potentially recognized by melanoma differentiation-associated protein 5 (MDA5) as non-self. Of note, loss-of-function mutations in the ADAR1 gene cause Aicardi-Goutières syndrome, a congenital autoimmune disease characterized by encephalopathy and a type I interferon (IFN) signature. However, the loss of ADAR1 in cancer cells with an IFN signature induces lethality via the activation of protein kinase R in addition to MDA5. This makes cells more sensitive to immunotherapy, highlighting the opposing immune status of autoimmune diseases (overreaction) and cancer (tolerance). In this review, we provide an overview of insights into two opposing aspects of RNA editing that functions as a modulator of the immune system in autoimmune diseases and cancer.


Assuntos
Adenosina/metabolismo , Sistema Imunitário/metabolismo , Inosina/metabolismo , Edição de RNA , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/patologia , Humanos , Neoplasias/genética , Neoplasias/patologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia
10.
Dev Med Child Neurol ; 62(1): 42-47, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175662

RESUMO

Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi-Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy. WHAT THIS PAPER ADDS: Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment. Further rational therapies are expected to become available in the short- to medium-term.


Assuntos
Doenças Autoimunes do Sistema Nervoso/terapia , Malformações do Sistema Nervoso/terapia , Doenças Autoimunes do Sistema Nervoso/etiologia , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Humanos , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia
11.
Brain ; 143(2): 491-502, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851307

RESUMO

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43-77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.


Assuntos
Encefalopatias/genética , Encéfalo/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Endoteliais/metabolismo , Adulto , Encéfalo/patologia , Encefalopatias/metabolismo , Calcinose/genética , Feminino , Genes Recessivos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Linhagem , Fenótipo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
12.
Am J Hum Genet ; 105(5): 1005-1015, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31630790

RESUMO

Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and other GCPs to regulate the assembly of microtubules. By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.


Assuntos
Variação Genética/genética , Lisencefalia/genética , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/genética , Alelos , Encéfalo/metabolismo , Movimento Celular/genética , Criança , Exoma/genética , Feminino , Homozigoto , Humanos , Masculino , Microtúbulos/genética , Malformações do Sistema Nervoso/genética , Neurônios/metabolismo , Fenótipo , Tubulina (Proteína)/genética
13.
Commun Biol ; 2: 375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31633066

RESUMO

Synaptosomal-associated protein 29 (SNAP29) encodes a member of the SNARE family of proteins implicated in numerous intracellular protein trafficking pathways. SNAP29 maps to the 22q11.2 region and is deleted in 90% of patients with 22q11.2 deletion syndrome (22q11.2DS). Moreover, bi-allelic SNAP29 mutations in patients are responsible for CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome. A mouse model that recapitulates abnormalities found in these syndromes is essential for uncovering the cellular basis of these disorders. In this study, we report that mice with a loss of function mutation of Snap29 on a mixed CD1;FvB genetic background recapitulate skin abnormalities associated with CEDNIK, and also phenocopy neurological and ophthalmological abnormalities found in CEDNIK and a subset of 22q11.2DS patients. Our work also reveals an unanticipated requirement for Snap29 in male fertility and supports contribution of hemizygosity for SNAP29 to the phenotypic spectrum of abnormalities found in 22q11.2DS patients.


Assuntos
Síndrome de DiGeorge/genética , Ceratodermia Palmar e Plantar/genética , Síndromes Neurocutâneas/genética , Proteínas Qb-SNARE/deficiência , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/deficiência , Proteínas Qc-SNARE/genética , Animais , Síndrome de DiGeorge/patologia , Síndrome de DiGeorge/fisiopatologia , Modelos Animais de Doenças , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Hemizigoto , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Ceratodermia Palmar e Plantar/patologia , Ceratodermia Palmar e Plantar/fisiopatologia , Mutação com Perda de Função , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/patologia , Síndromes Neurocutâneas/patologia , Síndromes Neurocutâneas/fisiopatologia , Fenótipo , Gravidez
14.
J Biochem ; 166(6): 537-545, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31529068

RESUMO

Mammalian RNase H2 is a heterotrimeric enzyme consisting of one catalytic subunit (A) and two accessory subunits (B and C). RNase H2 is involved in the removal of a single ribonucleotide embedded in genomic DNA and removal of RNA of RNA/DNA hybrids. In humans, mutation of the RNase H2 gene causes a severe neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). Here, we examined the activity and stability of six recombinant human RNase H2 variants bearing one AGS-causing mutation, A-G37S (Gly37 in the A subunit is replaced with Ser), A-N212I, A-R291H, B-A177T, B-V185G, or C-R69W. The activity of A-G37S was 0.3-1% of that of the wild-type RNase H2 (WT), while those of other five variants were 51-120%. In circular dichroism measurement, the melting temperatures of variants were 50-53°C, lower than that of WT (56°C). These results suggested that A-G37S had decreased activity and stability than WT, while other five variants had decreased stability but retained activity. In gel filtration chromatography of the purified enzyme preparation, WT migrated as a heterotrimer, while A-R291H eluted in two separate peaks containing either the heterotrimer or only the A subunit, suggesting that some AGS-causing mutations affect the heterotrimer-forming stability of RNase H2.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , Malformações do Sistema Nervoso/genética , Ribonuclease H/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Humanos , Mutação , Malformações do Sistema Nervoso/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ribonuclease H/química , Ribonuclease H/metabolismo
15.
Orphanet J Rare Dis ; 14(1): 184, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349848

RESUMO

BACKGROUND: Ribonucleases (RNases) are crucial for degradation of ribosomal RNA (rRNA). RNASET2 as a subtype of RNASEs is a 256 amino acid protein, encoded by RNASET2 gene located on chromosome six. Defective RNASET2 leads to RNASET2-deficient leukoencephalopathy, a rare autosomal recessive neurogenetic disorder with psychomotor delay as its main clinical symptom. The clinical findings can be similar to congenital cytomegalovirus (CMV) infection and Aicardi-Goutieres syndrome (AGS). METHODS: Herein, we presented a patient with motor delay, neurological regression, infrequent seizures and microcephaly at 5 months of age. Brain imaging showed white matter involvement, calcification and anterior temporal cysts. Basic metabolic tests, serum and urine CMV polymerase chain reaction (PCR) were requested. According to clinical and imaging findings, screening of RNASET2 and RMND1 genes were performed. The clinical data and magnetic resonance imaging (MRI) findings of previous reported individuals with RNASET2-deficient leukodystrophy were also reviewed and compared to the findings of our patient. RESULTS: Brain MRI findings were suggestive of RNASET2-deficient leukoencephalopathy, AGS and CMV infection. Basic metabolic tests were normal and CMV PCR was negative. Molecular study revealed a novel homozygous variant of c.233C > A; p.Ser78Ter in exon 4 of RNASET2 gene compatible with the diagnosis of RNASET2-deficient leukoencephalopathy. CONCLUSIONS: RNASET2-deficiency is a possible diagnosis in an infant presented with a static leukoencephalopathy and white matter involvement without megalencephaly. Due to overlapping clinical and radiologic features of RNASET2-deficient leukoencephalopathy, AGS and congenital CMV infections, molecular study as an important and helpful diagnostic tool should be considered to avoid misdiagnosis.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Infecções por Citomegalovirus/diagnóstico , Leucoencefalopatias/diagnóstico , Malformações do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Pré-Escolar , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/metabolismo , Feminino , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Imagem por Ressonância Magnética , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Gravidez , Ribonucleases/genética , Ribonucleases/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
16.
Pediatr Dev Pathol ; 22(6): 546-557, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256740

RESUMO

OBJECTIVES: Central nervous system (CNS) anomalies are the second most frequent category of congenital anomalies after congenital heart defects (CHDs). In this study, the aim was to investigate the distribution of different CNS anomalies with associated anomalies and karyotype in a fetal autopsy population of terminated pregnancies over a 30-year period and to correlate the ultrasonographic diagnoses of CNS anomalies with autopsy findings. MATERIALS AND METHODS: This study includes 420 intact fetuses with CNS anomalies terminated at gestational ages 11+ 0 to 33+ 6 over a 30-year period from 1985 to 2014. An ultrasound (US) examination was performed at the National Centre for Fetal Medicine, St. Olavs Hospital, Trondheim. The autopsies were performed at the Department of Pathology at the same hospital or a collaborating hospital. The anomalies were subcategorized according to the classification by the World Health Organization. RESULTS: Neural tube defects such as anencephaly (22.4%, 107/477) and spina bifida (22.2%, 106/477) constituted the most common CNS anomalies, followed by congenital hydrocephalus (17.8%, 85/477). In total, the karyotype was abnormal in 21.0% of all termination of pregnancies (TOPs), with trisomy 18 as the most frequent abnormal karyotype. CHDs, skeletal anomalies, and urinary anomalies were the most common associated organ anomalies. Throughout the study period, there was full agreement between US and postmortem findings of CNS anomalies in 96.9% (407/420) of TOPs. CONCLUSION: In this study of autopsy findings of CNS anomalies in intact fetuses terminated after prenatal US diagnosis, neural tube defects were most common. About half of the fetuses had isolated serious CNS anomalies, while the other half were CNS anomalies associated with structural and/or chromosomal anomalies. The prenatal US diagnoses were in good concordance with autopsy findings. In particular, due to challenges of diagnoses made early in pregnancy, it is necessary to continue the validation practice.


Assuntos
Aborto Eugênico , Sistema Nervoso Central/anormalidades , Malformações do Sistema Nervoso/patologia , Ultrassonografia Pré-Natal , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/patologia , Feminino , Humanos , Cariótipo , Masculino , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/embriologia , Malformações do Sistema Nervoso/genética , Gravidez
17.
Am J Hum Genet ; 105(2): 413-424, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327508

RESUMO

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.


Assuntos
Transtornos Dismórficos Corporais/patologia , Cerebelo/anormalidades , Coloboma/patologia , Deficiências do Desenvolvimento/patologia , Epilepsia/patologia , Deficiência Intelectual/patologia , Mutação , Malformações do Sistema Nervoso/patologia , Repetições WD40/genética , Adulto , Sequência de Aminoácidos , Animais , Transtornos Dismórficos Corporais/genética , Cerebelo/patologia , Criança , Coloboma/genética , Deficiências do Desenvolvimento/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Epilepsia/genética , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Malformações do Sistema Nervoso/genética , Fenótipo , Homologia de Sequência , Adulto Jovem
18.
Eur J Med Genet ; 62(8): 103704, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207318

RESUMO

Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.


Assuntos
Encéfalo/fisiopatologia , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Proteínas de Transporte Vesicular/genética , Encéfalo/diagnóstico por imagem , Criança , Endossomos/genética , Feminino , Humanos , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/fisiopatologia , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/fisiopatologia , Transporte Proteico/genética , Rede trans-Golgi/genética
19.
BMJ Case Rep ; 12(5)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133547

RESUMO

Several genes located within the chromosome 8p11.21 region are associated with movement disorders including SLC20A2 and THAP1. SLC20A2 is one of four genes associated with primary familial brain calcification, a syndrome that also includes movement disorders, cognitive decline and psychiatric issues. THAP1 is associated with dystonia type 6, a dominantly inherited dystonia with variable expression. In addition, several reports in the French-Canadian population have described microdeletions within the 8p11.2 region presenting with dystonia-plus syndromes including brain calcifications. This case report describes a 12-year-old boy with brain calcifications and generalised dystonia associated with a deletion in the 8p11.2 region detected via single nucleotide polymorphism microarray. This report emphasises the importance of obtaining a microarray analysis in diagnosing movement disorders and suggests that this copy number variant may be an under-recognised cause of dystonia and brain calcifications.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Distonia/diagnóstico , Malformações do Sistema Nervoso/genética , Proteínas Reguladoras de Apoptose , Calcinose/diagnóstico por imagem , Calcinose/patologia , Criança , Cromossomos Humanos Par 2/genética , Proteínas de Ligação a DNA , Distonia/genética , Deleção de Genes , Haploinsuficiência/genética , Heterozigoto , Humanos , Masculino , Análise em Microsséries/métodos , Transtornos dos Movimentos/genética , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Polimorfismo de Nucleotídeo Único , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III
20.
PLoS Genet ; 15(5): e1008020, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31125342

RESUMO

Breast cancer is the second leading cause of cancer-related deaths in the United States, with the majority of these deaths due to metastatic lesions rather than the primary tumor. Thus, a better understanding of the etiology of metastatic disease is crucial for improving survival. Using a haplotype mapping strategy in mouse and shRNA-mediated gene knockdown, we identified Rnaseh2c, a scaffolding protein of the heterotrimeric RNase H2 endoribonuclease complex, as a novel metastasis susceptibility factor. We found that the role of Rnaseh2c in metastatic disease is independent of RNase H2 enzymatic activity, and immunophenotyping and RNA-sequencing analysis revealed engagement of the T cell-mediated adaptive immune response. Furthermore, the cGAS-Sting pathway was not activated in the metastatic cancer cells used in this study, suggesting that the mechanism of immune response in breast cancer is different from the mechanism proposed for Aicardi-Goutières Syndrome, a rare interferonopathy caused by RNase H2 mutation. These results suggest an important novel, non-enzymatic role for RNASEH2C during breast cancer progression and add Rnaseh2c to a panel of genes we have identified that together could determine patients with high risk for metastasis. These results also highlight a potential new target for combination with immunotherapies and may contribute to a better understanding of the etiology of Aicardi-Goutières Syndrome autoimmunity.


Assuntos
Imunidade Adaptativa , Doenças Autoimunes do Sistema Nervoso/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Malformações do Sistema Nervoso/genética , Ribonuclease H/genética , Animais , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/mortalidade , Doenças Autoimunes do Sistema Nervoso/patologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metástase Linfática , Camundongos , Camundongos Nus , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Malformações do Sistema Nervoso/imunologia , Malformações do Sistema Nervoso/mortalidade , Malformações do Sistema Nervoso/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Ribonuclease H/antagonistas & inibidores , Ribonuclease H/imunologia , Análise de Sequência de RNA , Transdução de Sinais , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/patologia
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