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1.
Hum Genet ; 139(4): 513-519, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31960134

RESUMO

Arthrogryposis multiplex congenita (AMC) is an important birth defect with a significant genetic contribution. Many syndromic forms of AMC have been described, but remain unsolved at the molecular level. In this report, we describe a novel syndromic form of AMC in two multiplex consanguineous families from Saudi Arabia and Oman. The phenotype is highly consistent, and comprises neurogenic arthrogryposis, microcephaly, brain malformation (absent corpus callosum), optic atrophy, limb fractures, profound global developmental delay, and early lethality. Whole-exome sequencing revealed a different homozygous truncating variant in SCYL2 in each of the two families. SCYL2 is a component of clathrin-coated vesicles, and deficiency of its mouse ortholog results in a severe neurological phenotype that largely recapitulates the phenotype observed in our patients. Our results suggest that severe neurogenic arthrogryposis with brain malformation is the human phenotypic consequence of SCYL2 loss of function mutations.


Assuntos
Artrogripose , Genes Recessivos , Mutação com Perda de Função , Linhagem , Proteínas Serina-Treonina Quinases/genética , Adulto , Artrogripose/diagnóstico por imagem , Artrogripose/genética , Artrogripose/patologia , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome
2.
Eur J Med Genet ; 63(1): 103624, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30690204

RESUMO

The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.


Assuntos
Artrogripose/genética , Hidropisia Fetal/genética , Microcefalia/genética , Enxaqueca com Aura/genética , ATPase Trocadora de Sódio-Potássio/genética , Alelos , Animais , Artrogripose/patologia , Criança , Feminino , Predisposição Genética para Doença , Humanos , Hidropisia Fetal/patologia , Recém-Nascido , Mutação com Perda de Função/genética , Masculino , Camundongos , Microcefalia/patologia , Enxaqueca com Aura/patologia , Fenótipo , Gravidez , Isoformas de Proteínas/genética , Sequenciamento Completo do Exoma
3.
Mol Med Rep ; 21(1): 438-444, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746383

RESUMO

Distal arthrogryposis (DA) type 2B (DA2B) is an autosomal dominant congenital disorder, characterized by camptodactyly, thumb adduction, ulnar deviation and facial features, including small mouth, down­slanting palpebral fissure and slight nasolabial fold. It has been reported that four genes are associated with DA2B, including troponin I, fast­twitch skeletal muscle isoform, troponin T3, fast skeletal, myosin heavy chain 3 (MYH3) and tropomyosin 2, which are all associated with embryonic limb morphogenesis and skeletal muscle contraction. In the present study, three affected family members and five unaffected individuals were identified through clinical and radiological assessment. Genomic DNA was obtained from the three patients, which then underwent whole­exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and 100 healthy volunteers. Then, the spatial models of embryonic MYH were further constructed. In the clinic, the three patients recruited to the present study were diagnosed with DA2B. Mutation analysis indicated that there was a novel heterogeneous missense mutation c.2506 A>G (p.K836E) in the MYH3 gene among the affected individuals, which was highly conserved and was not identified in the unaffected family members and healthy controls. Furthermore, protein modeling revealed that the altered position interacted with regulatory light chain. Thus, the present study identified a novel pathogenic mutation of the MYH3 gene in a Chinese family with DA2B, which expanded the mutational spectrum of MYH3 and provided additional information regarding the association between mutation locations and different types of DA.


Assuntos
Artrogripose/genética , Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Contração Muscular/genética , Adolescente , Adulto , Artrogripose/sangue , Artrogripose/patologia , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Sequenciamento Completo do Exoma , Adulto Jovem
4.
Am J Hum Genet ; 105(4): 689-705, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31495489

RESUMO

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.


Assuntos
Artrogripose/genética , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Esfingomielina Fosfodiesterase/genética , Artrogripose/patologia , Linhagem da Célula , Criança , Retículo Endoplasmático/metabolismo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Microcefalia/patologia , Mitose , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Processamento de RNA
5.
Am J Med Genet C Semin Med Genet ; 181(3): 345-353, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31410997

RESUMO

Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X-linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.


Assuntos
Artrogripose/diagnóstico , Artrogripose/patologia , Encéfalo/patologia , Artrogripose/genética , Eletroencefalografia/métodos , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Imagem por Ressonância Magnética/métodos , Medula Espinal/patologia
6.
Am J Med Genet C Semin Med Genet ; 181(3): 280-287, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31452331

RESUMO

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent. Some have described it as a diagnosis or syndrome, others as a term or clinical finding. This lack of common language can lead to confusion in clinical and research communities. The aim of this study was to develop a consensus-based definition for AMC using international expert opinion. A consensus-based definition will help harmonize research and clinical endeavors and will facilitate communication among families, clinicians, and researchers. This article describes the methodology used leading to a proposed definition of AMC. First, a literature review was conducted to identify AMC definitions used in included studies. The most commonly used words in the definitions were extracted. Second, a group of eight experts in AMC was selected to identify elements considered critically important to the definition of AMC. Third, based on these critical elements and the literature review, a definition was drafted by the research team. Fourth, a modified Delphi consensus process was conducted using electronic surveys with 25 experts in the field of AMC from eight countries. Survey results were analyzed quantitatively and qualitatively and drafts were modified accordingly. Three rounds of surveys were completed until consensus was reached on a definition of AMC. An annotation of this definition, developed by a panel of international experts, is provided in a separate manuscript in this special issue.


Assuntos
Artrogripose/patologia , Consenso , Humanos , Inquéritos e Questionários
7.
Am J Hum Genet ; 105(1): 132-150, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31230720

RESUMO

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.


Assuntos
Artrogripose/genética , Artrogripose/patologia , Variações do Número de Cópias de DNA , Marcadores Genéticos , Genômica/métodos , Herança Multifatorial/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Conectina/genética , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Mosaicismo , Linhagem , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Proteínas de Transporte Vesicular/genética , Sequenciamento Completo do Exoma , Adulto Jovem
8.
Am J Med Genet C Semin Med Genet ; 181(3): 277-279, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31120641

RESUMO

The 1st international symposium on arthrogryposis (ISA) was held in 2007 in Birmingham, UK, to bring together a multinational group of experts in the field of arthrogryposis, patients and their families to discuss various aspects of care for individuals with Arthrogryposis Multiplex Congenita (AMC). These "lessons learnt" set the tone for the 2nd ISA held in Saint Petersburg, Russia in 2014. Clinical and research advances have recently been made in the field of arthrogryposis and were shared at the 3rd ISA, in Philadelphia, in 2018. Highlights of the 3ISA and future directions are presented.


Assuntos
Artrogripose/patologia , Humanos
9.
J Matern Fetal Neonatal Med ; 32(3): 502-511, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28954562

RESUMO

Arthrogryposis multiplex congenita (AMC) refers to the development of multiple joint contractures affecting two or more areas of the body prior to birth. It affects approximately 1 in 3000 individuals, mostly reported in individuals of Asian, African and European descent with equal incidence in males and females. Arthrogryposis is associated with over 400 medical conditions and 350 known genes with considerable variability in phenotypic expression. The primary underlying mechanism is decreased fetal movement during development. Prenatal imaging is crucial in early diagnosis by identifying fetal movement limitations and the presence of club foot or joint contractures. Postnatal autopsy confirms the diagnosis and extent of associated congenital anomalies and provides a valuable source of DNA material. Molecular methods are particularly useful in delineating novel gene mutations, locus heterogeneity and phenotype genotype correlation. Prenatal evaluation with early diagnosis via image scanning and further genetic surveillance give the opportunity for family counseling concerning future pregnancy management and expected neonatal morbidity and mortality.


Assuntos
Artrogripose/diagnóstico , Artrogripose/patologia , Artrogripose/epidemiologia , Artrogripose/genética , Feminino , Estudos de Associação Genética , Humanos , Fenótipo , Gravidez , Ultrassonografia Pré-Natal
10.
Hum Genet ; 138(1): 105-107, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30483960

RESUMO

ISLR2 (immunoglobulin superfamily containing leucine-rich repeat 2), encodes a protein involved in axon guidance in brain development (hence the other name leucine-rich repeat domain- and immunoglobulin domain-containing axon extension proteins; LINX). A recently described mouse knockout displays hydrocephalus. However, the corresponding phenotype in humans is unknown. Here, we describe a multiplex consanguineous family in which a homozygous truncating variant in ISLR2 segregates with severe congenital hydrocephalus, arthrogryposis multiplex congenita and abdominal distension. We suggest this syndrome may represent the human "knockout" phenotype for ISLR2.


Assuntos
Abdome/anormalidades , Artrogripose/genética , Biomarcadores/análise , Deleção de Genes , Genes Recessivos , Hidrocefalia/genética , Imunoglobulinas/genética , Abdome/patologia , Artrogripose/patologia , Feminino , Homozigoto , Humanos , Hidrocefalia/patologia , Lactente , Masculino , Linhagem , Fenótipo , Prognóstico , Síndrome
11.
Clin Dysmorphol ; 28(1): 17-21, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30303820

RESUMO

Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144-1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM_000158). Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum.


Assuntos
Artrogripose/enzimologia , Artrogripose/genética , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Doença de Depósito de Glicogênio Tipo IV/genética , Mutação/genética , Doenças Neuromusculares/enzimologia , Doenças Neuromusculares/genética , Artrogripose/patologia , Sequência de Bases , Feminino , Feto/patologia , Doença de Depósito de Glicogênio Tipo IV/patologia , Humanos , Recém-Nascido , Masculino , Doenças Neuromusculares/patologia , Linhagem
12.
Eur J Med Genet ; 62(9): 103544, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30244176

RESUMO

Heterozygous mutations in TOR1A gene are known to be responsible for DYT1 dystonia with incomplete penetrance. Autosomal recessive TOR1A disease is a very recently described syndrome characterized by severe arthrogryposis, developmental delay, strabismus and tremor. A 2 month-old boy with severe arthrogryposis and developmental delay was referred to our department for genetic counseling. Dystonic movements were observed on physical examination. Whole exome sequencing revealed a homozygous nonsense variant in exon 5 of TOR1A (c.862C > T, p.Arg288*). Our results expand the phenotypic and mutational spectrum of biallelic TOR1A disease, while emphasizing the importance of reverse phenotyping in the diagnosis of rare genetic disorders.


Assuntos
Artrogripose/genética , Códon sem Sentido , Chaperonas Moleculares/genética , Alelos , Artrogripose/patologia , Testes Genéticos/métodos , Testes Genéticos/normas , Humanos , Lactente , Masculino , Penetrância , Sequenciamento Completo do Exoma
13.
Int J Mol Sci ; 19(8)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071673

RESUMO

Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.


Assuntos
Artrogripose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/genética , Processamento de RNA/genética , Fator C de Crescimento do Endotélio Vascular/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Artrogripose/metabolismo , Artrogripose/patologia , Pré-Escolar , Fissura Palatina/metabolismo , Fissura Palatina/patologia , Pé Torto Equinovaro/metabolismo , Pé Torto Equinovaro/patologia , Feminino , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Domínios Proteicos , Fator C de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
14.
Eur J Hum Genet ; 26(12): 1752-1758, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30089828

RESUMO

Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodegenerative disorder with a prenatal onset. Using whole-exome sequencing, we identified variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis, in four individuals from two families with PCH, prenatal onset microcephaly, and arthrogryposis. In family 1, compound heterozygous variants were identified in COASY: c.[1549_1550delAG]; [1486-3 C>G]. In family 2, all three affected siblings were homozygous for the c.1486-3 C>G variant. In both families, the variants segregated with the phenotype. RNA analysis showed that the c.1486-3 C>G variant leads to skipping of exon 7 with partial retention of intron 7, disturbing the reading frame and resulting in a premature stop codon (p.(Ala496Ilefs*20)). No CoA synthase protein was detected in patient cells by immunoblot analysis and CoA synthase activity was virtually absent. Partial CoA synthase defects were previously described as a cause of COASY Protein-Associated Neurodegeneration (CoPAN), a type of Neurodegeneration and Brain Iron Accumulation (NBIA). Here we demonstrate that near complete loss of function variants in COASY are associated with lethal PCH and arthrogryposis.


Assuntos
Artrogripose/genética , Doenças Cerebelares/genética , Mutação com Perda de Função , Microcefalia/genética , Transferases/genética , Feto Abortado/anormalidades , Artrogripose/patologia , Células Cultivadas , Doenças Cerebelares/patologia , Humanos , Recém-Nascido , Masculino , Microcefalia/patologia , Síndrome , Transferases/metabolismo
15.
Biosci Rep ; 38(5)2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30104399

RESUMO

Platelets respond to vascular injury via surface receptor stimulation and signaling events to trigger aggregation, procoagulant activation, and granule secretion during hemostasis, thrombosis, and vascular remodeling. Platelets contain three major types of secretory granules including dense granules (or δ-granules, DGs), α-granules (AGs), and lysosomes. The contents of platelet granules are specific. Platelet DGs store polyphosphate and small molecules such as ADP, ATP, Ca2+, and serotonin, while AGs package most of the proteins that platelets release. The platelet DGs and AGs are regarded as being budded from the endosomes and the trans-Golgi network (TGN), respectively, and then matured from multivesicular bodies (MVBs). However, the sorting machineries between DGs and AGs are different. Inherited platelet disorders are associated with deficiency of DGs and AGs, leading to bleeding diathesis in patients with Hermansky-Pudlak syndrome (HPS), gray platelet syndrome (GPS), and arthrogryposis, renal dysfunction, and cholestasis syndrome (ARC). Here, we reviewed the current understanding about how DGs differ from AGs in structure, biogenesis, and function. In particular, we focus on the sorting machineries that are involved in the formation of these two types of granules to provide insights into their diverse biological functions.


Assuntos
Plaquetas/metabolismo , Grânulos Citoplasmáticos/metabolismo , Corpos Multivesiculares/metabolismo , Vesículas Secretórias/metabolismo , Artrogripose/metabolismo , Artrogripose/patologia , Plaquetas/patologia , Colestase/metabolismo , Colestase/patologia , Grânulos Citoplasmáticos/genética , Endossomos/metabolismo , Síndrome da Plaqueta Cinza/metabolismo , Síndrome da Plaqueta Cinza/patologia , Síndrome de Hermanski-Pudlak/metabolismo , Síndrome de Hermanski-Pudlak/patologia , Humanos , Lisossomos/metabolismo , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia , Vesículas Secretórias/genética , Rede trans-Golgi/genética
16.
Artigo em Inglês | MEDLINE | ID: mdl-30054298

RESUMO

We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.


Assuntos
Artrogripose/genética , Proteínas Associadas aos Microtúbulos/genética , Atrofia Muscular/genética , Artrogripose/patologia , Sequência de Bases/genética , Criança , Exoma/genética , Feminino , Humanos , Cinesina/fisiologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/fisiologia , Atrofia Muscular/patologia , Mutação/genética , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
18.
Int J Mol Med ; 42(4): 2238-2246, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30015832

RESUMO

The present study aimed to identify the molecular basis of the arthrogryposis­renal dysfunction­cholestasis (ARC) syndrome, which is caused by mutations in the vacuolar protein sorting 33 homolog B (VPS33B) gene. The microarray dataset GSE83192, which contained six liver tissue samples from VPS33B knockout mice and four liver tissue samples from control mice, was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were screened by the Limma package in R software. The DEGs most relevant to ARC were selected via weighted gene co­expression network analysis to construct a protein­protein interaction (PPI) network. In addition, module analysis was performed for the PPI network using the Molecular Complex Detection function. Functional and pathway enrichment analyses were also performed for DEGs in the PPI network. Potential drugs for ARC treatment were predicted using the Connectivity Map database. In total, 768 upregulated and 379 downregulated DEGs were detected in the VPS33B knockout mice, while three modules were identified from the PPI network constructed. The DEGs in module 1 (CD83, IL1B and TLR2) were mainly involved in the positive regulation of cytokine production and the Toll­like receptor (TLR) signaling pathway. The DEGs in module 2 (COL1A1 and COL1A2) were significantly enriched with respect to cellular component organization, extracellular matrix­receptor interactions and focal adhesion. The DEGs in module 3 (ABCG8 and ABCG3) were clearly associated with sterol absorption and transport. Furthermore, mercaptopurine was identified to be a potential drug (connectivity score=­0.939) for ARC treatment. In conclusion, the results of the current study may help to further understand the pathology of ARC, and the DEGs identified in these modules may serve as therapeutic targets.


Assuntos
Artrogripose , Colestase , Redes Reguladoras de Genes , Insuficiência Renal , Transdução de Sinais/genética , Animais , Artrogripose/genética , Artrogripose/metabolismo , Artrogripose/patologia , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Camundongos , Camundongos Knockout , Insuficiência Renal/genética , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia
19.
Brain Dev ; 40(9): 760-767, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29803542

RESUMO

OBJECTIVE: To reveal a molecular lesion in the ZC4H2 gene in a Japanese family with arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), and to characterize clinical features of patients with ZC4H2 gene mutations through a literature review. PATIENTS: The probands are male siblings. The elder brother is an 11-year-old boy who showed AMC and ID and frequent postprandial hypoglycemia since 3 years of age. The younger brother also showed AMC, ID, and subclinical postprandial hypoglycemia. The boys' mother also showed a minor malformation of the left toes. METHOD AND RESULT: Using Sanger sequencing, a hemizygous one base substitution designated c.627G > C, which is predicted to substitute asparagine for lysine at amino acid residue 209 (K209N), was identified in the siblings. The mother was heterozygous for this mutation. In silico analysis predicted K209N to be a constituent of a motif required for subcellular localization of the ZC4H2 protein in the nucleus. Transient expression studies of subcellular localization in COS-7 cells showed that compared to the wild-type protein, the transport of the mutant protein into the nucleus was inhibited, thus confirming K209N as a molecular lesion in this family. The literature reviews revealed postprandial hypoglycemia as a new clinical feature that should be considered in ZC4H2 gene-mutation disorders. CONCLUSION: A Japanese family with AMC and ID caused by a novel ZC4H2 gene mutation was reported. Hypoglycemia should be considered one of the features in this disorder.


Assuntos
Artrogripose/genética , Proteínas de Transporte/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Artrogripose/patologia , Artrogripose/fisiopatologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Criança , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas Nucleares , Fenótipo , Irmãos
20.
Biochim Biophys Acta Mol Basis Dis ; 1864(5 Pt A): 1609-1621, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29409756

RESUMO

Mutations in VPS33B and VIPAS39 cause the severe multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome. Amongst other symptoms, patients with ARC syndrome suffer from severe ichthyosis. Roles for VPS33B and VIPAR have been reported in lysosome-related organelle biogenesis, integrin recycling, collagen homeostasis and maintenance of cell polarity. Mouse knockouts of Vps33b or Vipas39 are good models of ARC syndrome and develop an ichthyotic phenotype. We demonstrate that the skin manifestations in Vps33b and Vipar deficient mice are histologically similar to those of patients with ARC syndrome. Histological, immunofluorescent and electron microscopic analysis of Vps33b and Vipar deficient mouse skin biopsies and isolated primary cells showed that epidermal lamellar bodies, which are essential for skin barrier function, had abnormal morphology and the localisation of lamellar body cargo was disrupted. Stratum corneum formation was affected, with increased corneocyte thickness, decreased thickness of the cornified envelope and reduced deposition of lipids. These defects impact epidermal homeostasis and lead to abnormal barrier formation causing the skin phenotype in Vps33b and Vipar deficient mice and patients with ARC syndrome.


Assuntos
Artrogripose , Colestase , Epiderme , Insuficiência Renal , Proteínas de Transporte Vesicular , Animais , Artrogripose/genética , Artrogripose/metabolismo , Artrogripose/patologia , Colestase/genética , Colestase/metabolismo , Colestase/patologia , Modelos Animais de Doenças , Epiderme/metabolismo , Epiderme/patologia , Humanos , Camundongos , Camundongos Knockout , Insuficiência Renal/genética , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
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