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1.
Immunity ; 53(3): 672-684.e11, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32750333

RESUMO

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.


Assuntos
Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/patologia , Janus Quinase 1/genética , Síndrome de Resposta Inflamatória Sistêmica/genética , Síndrome de Resposta Inflamatória Sistêmica/patologia , Adolescente , COVID-19/mortalidade , Domínio Catalítico/genética , Linhagem Celular , Citocinas/metabolismo , Feminino , Mutação com Ganho de Função/genética , Genótipo , Células HEK293 , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Humanos , Janus Quinase 1/antagonistas & inibidores , Mosaicismo , Piperidinas/uso terapêutico , Medicina de Precisão/métodos , Pirimidinas/uso terapêutico , Transdução de Sinais/imunologia , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico
2.
Clin Genet ; 104(3): 371-376, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37191084

RESUMO

NAA20 is the catalytic subunit of the NatB complex, which is responsible for N-terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20-related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N-terminal acetylation.


Assuntos
Microcefalia , Malformações do Sistema Nervoso , Adolescente , Humanos , Domínio Catalítico , Microcefalia/genética , Síndrome , Fenótipo , Acetiltransferase N-Terminal B/genética , Acetiltransferase N-Terminal B/metabolismo
3.
Am J Med Genet A ; 191(4): 1089-1093, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36579410

RESUMO

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism. We describe a patient identified through newborn screening in which the diagnosis of MADD was confirmed based on metabolic profiling, but clinical molecular sequencing of ETFA, ETFB, and ETFDH was normal. In order to identify the genetic etiology of MADD, we performed whole genome sequencing and identified a novel homozygous promoter variant in ETFA (c.-85G > A). Subsequent studies showed decreased ETFA protein expression in lymphoblasts. A promoter luciferase assay confirmed decreased activity of the mutant promoter. In both assays, the variant displayed considerable residual activity, therefore we speculate that our patient may have a late onset form of MADD (Type III). Our findings may be helpful in establishing a molecular diagnosis in other MADD patients with a characteristic biochemical profile but apparently normal molecular studies.


Assuntos
Proteínas Ferro-Enxofre , Deficiência Múltipla de Acil Coenzima A Desidrogenase , Recém-Nascido , Humanos , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Flavoproteínas Transferidoras de Elétrons/genética , Aminoácidos/genética , Homozigoto , Proteínas Ferro-Enxofre/genética , Mutação
4.
Am J Med Genet A ; 191(11): 2743-2748, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37675855

RESUMO

Moebius syndrome is a congenital cranial dysinnervation disorder (CCDD) that presents with nonprogressive cranial nerve (CN) VI and VII palsies resulting in facial weakness and inability to abduct the eye(s). While many CCDDs have an underlying genetic cause, the etiology of Moebius syndrome remains unclear as most cases are sporadic. Here, we describe a pair of monochorionic, diamniotic twin girls; one with normal growth and development, and one with micrognathia, reduced facial expression, and poor feeding. Magnetic resonance imaging of the brain performed on the affected twin at 19 months of age showed severely hypoplastic or absent CN IV bilaterally, left CN VI smaller than right, and bilateral hypoplastic CN VII and IX, consistent with a diagnosis of a CCDD, most similar to that of Moebius syndrome. Genomic sequencing was performed on each twin and data was assessed for discordant variants, as well as variants in novel and CCDD-associated genes. No pathogenic, likely pathogenic, or variants of uncertain significance were identified in genes known to be associated with CCDDs or other congenital facial weakness conditions. This family provides further evidence in favor of a stochastic event as the etiology in Moebius syndrome, rather than a monogenic condition.

5.
Hum Mutat ; 42(6): 685-693, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33783914

RESUMO

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.


Assuntos
Ataxia/genética , Hipotonia Muscular/genética , Fator de Transcrição Brn-3A/genética , Tremor/genética , Adulto , Ataxia/complicações , Ataxia/diagnóstico , Ataxia/patologia , Criança , Pré-Escolar , Feminino , Haploinsuficiência , Humanos , Imageamento por Ressonância Magnética , Masculino , Hipotonia Muscular/complicações , Hipotonia Muscular/diagnóstico , Mutação de Sentido Incorreto , Estudos Retrospectivos , Síndrome , Tremor/complicações , Tremor/diagnóstico , Estados Unidos , Sequenciamento do Exoma , Adulto Jovem
6.
Hum Genet ; 140(12): 1709-1731, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34652576

RESUMO

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.


Assuntos
Paralisia Facial/genética , Fibrose/genética , Mutação , Oftalmoplegia/genética , Doenças do Sistema Nervoso Periférico/genética , Tubulina (Proteína)/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Substituição de Aminoácidos , Arginina , Criança , Pré-Escolar , Paralisia Facial/diagnóstico , Paralisia Facial/fisiopatologia , Feminino , Fibrose/diagnóstico , Fibrose/fisiopatologia , Histidina , Humanos , Lactente , Masculino , Oftalmoplegia/diagnóstico , Oftalmoplegia/fisiopatologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Síndrome , Adulto Jovem
7.
Genet Med ; 23(11): 2213-2218, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34230638

RESUMO

PURPOSE: N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. In five individuals with overlapping phenotypes, we identified recessive homozygous missense variants in NAA20. METHODS: Two different NAA20 variants were identified in affected individuals in two consanguineous families by exome and genome sequencing. Biochemical studies were employed to assess the impact of the NAA20 variants on NatB complex formation and catalytic activity. RESULTS: Two homozygous variants, NAA20 p.Met54Val and p.Ala80Val (GenBank: NM_016100.4, c.160A>G and c.239C>T), segregated with affected individuals in two unrelated families presenting with developmental delay, intellectual disability, and microcephaly. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Thus, both NAA20 variants are impaired in their ability to perform cellular NatB-mediated N-terminal acetylation. CONCLUSION: We present here a report of pathogenic NAA20 variants causing human disease and data supporting an essential role for NatB-mediated N-terminal acetylation in human development and physiology.


Assuntos
Deficiência Intelectual , Microcefalia , Acetiltransferases , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Acetiltransferase N-Terminal B
8.
Muscle Nerve ; 63(4): 516-524, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33389762

RESUMO

INTRODUCTION: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. METHODS: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. RESULTS: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. DISCUSSION: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.


Assuntos
Paralisia Facial/congênito , Paralisia Facial/diagnóstico , Síndrome de Möbius/diagnóstico , Doenças Musculares/diagnóstico , Síndrome de Pierre Robin/diagnóstico , Adulto , Diagnóstico Diferencial , Paralisia Facial/genética , Paralisia Facial/fisiopatologia , Feminino , Heterozigoto , Humanos , Masculino , Síndrome de Möbius/genética , Síndrome de Möbius/fisiopatologia , Doenças Musculares/genética , Doenças Musculares/fisiopatologia , Mutação/genética , Síndrome de Pierre Robin/genética , Síndrome de Pierre Robin/fisiopatologia
9.
Brain ; 143(8): 2437-2453, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32761064

RESUMO

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.


Assuntos
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Deficiências do Desenvolvimento/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Doenças do Sistema Nervoso/genética , Humanos , Mutação , Fenótipo , Transporte Proteico/genética , Transdução de Sinais/genética
10.
Am J Hum Genet ; 101(2): 239-254, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777931

RESUMO

The synthesis of all 13 mitochondrial DNA (mtDNA)-encoded protein subunits of the human oxidative phosphorylation (OXPHOS) system is carried out by mitochondrial ribosomes (mitoribosomes). Defects in the stability of mitoribosomal proteins or mitoribosome assembly impair mitochondrial protein translation, causing combined OXPHOS enzyme deficiency and clinical disease. Here we report four autosomal-recessive pathogenic mutations in the gene encoding the small mitoribosomal subunit protein, MRPS34, in six subjects from four unrelated families with Leigh syndrome and combined OXPHOS defects. Whole-exome sequencing was used to independently identify all variants. Two splice-site mutations were identified, including homozygous c.321+1G>T in a subject of Italian ancestry and homozygous c.322-10G>A in affected sibling pairs from two unrelated families of Puerto Rican descent. In addition, compound heterozygous MRPS34 mutations were identified in a proband of French ancestry; a missense (c.37G>A [p.Glu13Lys]) and a nonsense (c.94C>T [p.Gln32∗]) variant. We demonstrated that these mutations reduce MRPS34 protein levels and the synthesis of OXPHOS subunits encoded by mtDNA. Examination of the mitoribosome profile and quantitative proteomics showed that the mitochondrial translation defect was caused by destabilization of the small mitoribosomal subunit and impaired monosome assembly. Lentiviral-mediated expression of wild-type MRPS34 rescued the defect in mitochondrial translation observed in skin fibroblasts from affected subjects, confirming the pathogenicity of MRPS34 mutations. Our data establish that MRPS34 is required for normal function of the mitoribosome in humans and furthermore demonstrate the power of quantitative proteomic analysis to identify signatures of defects in specific cellular pathways in fibroblasts from subjects with inherited disease.


Assuntos
DNA Mitocondrial/genética , Doença de Leigh/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Proteínas Ribossômicas/genética , Subunidades Ribossômicas Menores de Eucariotos/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Exoma/genética , Feminino , Humanos , Lactente , Doença de Leigh/enzimologia , Masculino , Mitocôndrias/genética , Fosforilação Oxidativa , Proteômica , Splicing de RNA/genética , Análise de Sequência de DNA
11.
Am J Med Genet A ; 182(5): 1263-1267, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134193

RESUMO

Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in NKX2.5, GATA4, TBX5, and CHD7. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0-kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37/hg19]) that included exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiopatias Congênitas/genética , Proteínas do Tecido Nervoso/genética , RNA Longo não Codificante/genética , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/fisiopatologia , Pré-Escolar , Deleção de Genes , Haploinsuficiência/genética , Coração/crescimento & desenvolvimento , Coração/fisiopatologia , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/fisiopatologia , Humanos , Masculino , Crista Neural/crescimento & desenvolvimento , Crista Neural/patologia , Estenose da Valva Pulmonar/diagnóstico por imagem , Estenose da Valva Pulmonar/genética , Estenose da Valva Pulmonar/fisiopatologia
12.
Hum Mutat ; 39(4): 563-578, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29314548

RESUMO

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.


Assuntos
Antígenos HLA/genética , Encefalomiopatias Mitocondriais , ATPases Mitocondriais Próton-Translocadoras/deficiência , Valina-tRNA Ligase/genética , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/metabolismo , Encefalomiopatias Mitocondriais/fisiopatologia , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Mutação de Sentido Incorreto , Fosforilação Oxidativa , Filogenia
13.
Hum Mutat ; 38(4): 373-377, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28054444

RESUMO

A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419* variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419* protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes-Brocks syndrome.


Assuntos
Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Anus Imperfurado , Códon sem Sentido , Perda Auditiva Neurossensorial , Proteínas Nucleares/genética , Polegar/anormalidades , Anormalidades Múltiplas/patologia , Animais , Genes Dominantes , Células HEK293 , Heterozigoto , Humanos , Camundongos Knockout , Análise de Sequência de DNA/métodos , Síndrome , Anormalidades Urogenitais , Xenopus
14.
Am J Med Genet A ; 173(10): 2763-2771, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28777491

RESUMO

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Síndrome de Möbius/genética , Doenças Musculares/genética , Mutação , Síndrome de Pierre Robin/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Síndrome de Möbius/complicações , Síndrome de Möbius/patologia , Doenças Musculares/complicações , Doenças Musculares/patologia , Linhagem , Síndrome de Pierre Robin/complicações , Síndrome de Pierre Robin/patologia , Prognóstico , Adulto Jovem
15.
J Med Genet ; 53(6): 389-96, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26792856

RESUMO

BACKGROUND/AIMS: Leukodystrophies due to abnormal production of myelin cause extensive morbidity in early life; their genetic background is still largely unknown. We aimed at reaching a molecular diagnosis in Ashkenazi-Jewish patients who suffered from developmental regression at 6-13 months, leukodystrophy and peripheral neuropathy. METHODS: Exome analysis, determination of alkaline ceramidase activity catalysing the conversion of C18:1-ceramide to sphingosine and D-ribo-C12-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-phytoceramide to NBD-C12-fatty acid using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and thin layer chromatography, respectively, and sphingolipid analysis in patients' blood by LC-MS/MS. RESULTS: The patients were homozygous for p.E33G in the ACER3, which encodes a C18:1-alkaline ceramidase and C20:1-alkaline ceramidase. The mutation abolished ACER3 catalytic activity in the patients' cells and failed to restore alkaline ceramidase activity in yeast mutant strain. The levels of ACER3 substrates, C18:1-ceramides and dihydroceramides and C20:1-ceramides and dihydroceramides and other long-chain ceramides and dihydroceramides were markedly increased in the patients' plasma, along with that of complex sphingolipids, including monohexosylceramides and lactosylceramides. CONCLUSIONS: Homozygosity for the p.E33G mutation in the ACER3 gene results in inactivation of ACER3, leading to the accumulation of various sphingolipids in blood and probably in brain, likely accounting for this new form of childhood leukodystrophy.


Assuntos
Ceramidase Alcalina/genética , Encefalopatias/genética , Azóis/metabolismo , Ceramidas/metabolismo , Criança , Pré-Escolar , Exoma/genética , Feminino , Humanos , Masculino , Nitrobenzenos/metabolismo , Doenças do Sistema Nervoso Periférico/genética , Esfingolipídeos/metabolismo , Esfingosina/metabolismo
17.
Cleft Palate Craniofac J ; 53(1): 126-31, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-25489769

RESUMO

OBJECTIVE: Comparison of global versus landmark analyses of facial asymmetry using three-dimensional photogrammetry to establish a precise method for evaluating facial asymmetry. DESIGN: The landmark-based approach utilized anthropometric data points. Our global approach involved registration of mirror images, independent of a midplane, to calculate a root mean square (RMS) value. We analyzed precision and technical and operator error of both methods. PARTICIPANTS: Three hundred fifty adults participated in this study. RESULTS: We found that the global method has better precision and repeatability with a significantly lower error rate than the landmark-based method. In adults, the average RMS was 0.6253 mm with a standard deviation of 0.16. CONCLUSIONS: Our facial asymmetry measurement is more accurate than landmark-based measurements. This method is quick, reliable, and results in generation of a RMS score and a corresponding color-coded facial map that highlights regions of higher and lower asymmetry. This method may be used as a screening tool for asymmetry in both the clinical and research settings.


Assuntos
Assimetria Facial/diagnóstico por imagem , Imageamento Tridimensional/métodos , Fotogrametria/métodos , Adulto , Pontos de Referência Anatômicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
18.
Hum Mutat ; 36(6): 587-92, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25754315

RESUMO

Novel, single-nucleotide mutations were identified in the mitochondrial methionyl amino-acyl tRNA synthetase gene (MARS2) via whole exome sequencing in two affected siblings with developmental delay, poor growth, and sensorineural hearing loss.We show that compound heterozygous mutations c.550C>T:p.Gln 184* and c.424C>T:p.Arg142Trp in MARS2 lead to decreased MARS2 protein levels in patient lymphoblasts. Analysis of respiratory complex enzyme activities in patient fibroblasts revealed decreased complex I and IV activities. Immunoblotting of patient fibroblast and lymphoblast samples revealed reduced protein levels of NDUFB8 and COXII, representing complex I and IV, respectively. Additionally, overexpression of wild-type MARS2 in patient fibroblasts increased NDUFB8 and COXII protein levels. These findings suggest that recessive single-nucleotide mutations in MARS2 are causative for a new mitochondrial translation deficiency disorder with a primary phenotype including developmental delay and hypotonia. Identification of additional patients with single-nucleotide mutations in MARS2 is necessary to determine if pectus carinatum is also a consistent feature of this syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Heterozigoto , Metionina tRNA Ligase/genética , Polimorfismo de Nucleotídeo Único , Sequência de Aminoácidos , Substituição de Aminoácidos , Encéfalo/patologia , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Genes Mitocondriais , Transtornos do Crescimento/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Metionina tRNA Ligase/química , Linhagem , Fenótipo
19.
Am J Hum Genet ; 91(1): 171-9, 2012 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-22770981

RESUMO

Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1(-/-) mouse phenotype. The missense variant is predicted to result in the substitution of a cysteine for an arginine at amino acid residue 207 (Arg207Cys), which corresponds to the highly conserved Arg5 of the homeodomain. Arg5 interacts with thymine in the minor groove of DNA through hydrogen bonding and electrostatic attraction. Molecular modeling and an in vitro DNA-protein binding assay predict that the mutation would disrupt these interactions, destabilize the HOXB1:PBX1:DNA complex, and alter HOXB1 transcriptional activity.


Assuntos
Paralisia Facial/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Homeodomínio/genética , Mutação de Sentido Incorreto , Estrabismo/genética , Animais , Sequência de Bases , Criança , Pré-Escolar , Feminino , Efeito Fundador , Humanos , Masculino , Camundongos , Síndrome de Möbius/genética , Modelos Moleculares , Linhagem , Fenótipo , Transcrição Gênica , Ativação Transcricional
20.
Brain ; 137(Pt 4): 1068-79, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24561559

RESUMO

Congenital facial weakness is present in a heterogeneous group of conditions. Among them is Moebius syndrome, which has been defined as a disorder with congenital, non-progressive facial weakness and limited abduction of one or both eyes. It is typically attributed to agenesis of the abducens and facial cranial nerves. This paper details ocular motor findings of 40 subjects (23 months to 64 years; 24 females, 16 males) with congenital facial weakness: 38 presented at a Moebius Syndrome Conference and two were clinic patients. A new classification scheme of patterns based on ocular motor phenotype is presented. Of 40 subjects, 37 had bilateral and three had unilateral facial weakness. The most common ocular motor pattern (Pattern 1, n=17, 43%) was bilateral horizontal gaze palsy with intact vertical range. Pattern 2 (n=10, 26%) was bilateral horizontal gaze palsy with variable vertical limitations. Pattern 3, which was rare, was isolated abduction deficits (n=2, 5%). Others had full motility range and did not meet minimal criteria for the diagnosis of Moebius syndrome (Pattern 4, n=10, 26%). One subject was too severely affected to characterize. Abnormal vertical smooth pursuit was present in 17 (57%) of 30 subjects: nine with Pattern 1, five with Pattern 2, and three with Pattern 4. Abnormal vertical saccades were present in 10 (34%) of 29 subjects. Vertical saccades appeared slow in nine: six with Pattern 1 and three with Pattern 2. Vertical saccades were absent in one subject with Pattern 2. Abnormal vertical optokinetic nystagmus was present in 19 (68%) of 28 subjects: 10 with Pattern 1, six with Pattern 2, one with Pattern 3, and two with Pattern 4. Reduced convergence was present in 19 (66%) of 29 subjects: nine with Pattern 1, six with Pattern 2, one with Pattern 3, and three with Pattern 4. The most common pattern of ocular motor deficit in Moebius syndrome is bilateral horizontal gaze palsy from pontine abducens nuclear defects, rather than abducens nerve involvement. Defects in the range or dynamic properties of vertical movements in subjects with congenital facial weakness may suggest involvement of ocular motor structures in the midbrain, including oculomotor nerves or nuclei, vertical supranuclear saccadic centres, and convergence neurons. Such deficits were found even in subjects with full vertical motility range. Classification of patterns of ocular motor deficits in congenital facial weakness may assist with further delineation of anatomic localization and identification of genetic deficits underlying these disorders.


Assuntos
Síndrome de Möbius/classificação , Síndrome de Möbius/fisiopatologia , Debilidade Muscular/fisiopatologia , Transtornos da Motilidade Ocular/classificação , Transtornos da Motilidade Ocular/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Movimentos Oculares , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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