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1.
Hum Mol Genet ; 32(6): 1032-1047, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36282544

RESUMO

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital condition characterized by aplasia or hypoplasia of the uterus and vagina in women with a 46,XX karyotype. This condition can occur as type I when isolated or as type II when associated with extragenital anomalies including kidney and skeletal abnormalities. The genetic basis of MRKH syndrome remains unexplained and several candidate genes have been proposed to play a role in its etiology, including HNF1B, LHX1 and WNT4. Here, we conducted a microarray analysis of 13 women affected by MRKH syndrome, resulting in the identification of chromosomal changes, including the deletion at 17q12, which contains both HNF1B and LHX1. We focused on HNF1B for further investigation due to its known association with, but unknown etiological role in, MRKH syndrome. We ablated Hnf1b specifically in the epithelium of the Müllerian ducts in mice and found that this caused hypoplastic development of the uterus, as well as kidney anomalies, closely mirroring the MRKH type II phenotype. Using single-cell RNA sequencing of uterine tissue in the Hnf1b-ablated embryos, we analyzed the molecules and pathways downstream of Hnf1b, revealing a dysregulation of processes associated with cell proliferation, migration and differentiation. Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype and generate the first mouse model of MRKH syndrome type II. Our results support the investigation of HNF1B in clinical genetic settings of MRKH syndrome and shed new light on the molecular mechanisms underlying this poorly understood condition in women's reproductive health.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual , Ductos Paramesonéfricos , Animais , Feminino , Camundongos , Transtornos 46, XX do Desenvolvimento Sexual/genética , Diferenciação Celular , Genômica , Fator 1-beta Nuclear de Hepatócito/genética , Humanos
2.
Am J Hum Genet ; 102(6): 1143-1157, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29805042

RESUMO

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.


Assuntos
Caderinas/genética , Cateninas/genética , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Mutação/genética , Alelos , Sequência de Aminoácidos , Animais , Biotinilação , Epitélio/metabolismo , Epitélio/patologia , Feminino , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Palato/patologia , Linhagem , Síndrome , Sequenciamento do Exoma , delta Catenina
3.
Am J Hum Genet ; 103(5): 666-678, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30343943

RESUMO

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.


Assuntos
Canais de Cálcio Tipo R/genética , Proteínas de Transporte de Cátions/genética , Contratura/genética , Discinesias/genética , Epilepsia/genética , Variação Genética/genética , Megalencefalia/genética , Espasmos Infantis/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/genética
4.
Am J Med Genet A ; 185(7): 2180-2189, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33878224

RESUMO

A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.


Assuntos
Aneurisma Aórtico/genética , Fibrilina-1/genética , Predisposição Genética para Doença , Síndrome de Marfan/genética , Idoso , Idoso de 80 Anos ou mais , Aneurisma Aórtico/complicações , Aneurisma Aórtico/patologia , Éxons , Feminino , Testes Genéticos , Humanos , Imunoglobulina G/genética , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Mutação
5.
Hum Mutat ; 41(1): 299-315, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31595648

RESUMO

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.


Assuntos
Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromina 1/genética , Substituição de Aminoácidos , Estudos Transversais , Heterozigoto , Humanos , Fenótipo
6.
Am J Hum Genet ; 100(6): 907-925, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575647

RESUMO

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.


Assuntos
Cromatina/metabolismo , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transcrição Gênica , Fator de Transcrição YY1/genética , Acetilação , Adolescente , Sequência de Bases , Pré-Escolar , Imunoprecipitação da Cromatina , Estudos de Coortes , Elementos Facilitadores Genéticos/genética , Feminino , Ontologia Genética , Haplótipos/genética , Hemizigoto , Histonas/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Domínios Proteicos , Fator de Transcrição YY1/química
7.
Mol Psychiatry ; 24(11): 1748-1768, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-29728705

RESUMO

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.


Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Transtorno da Conduta/genética , Feminino , Genes Ligados ao Cromossomo X , Células HEK293 , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Camundongos , Pessoa de Meia-Idade , Mutação , Linhagem , Fatores de Transcrição/genética , Ubiquitinação , Inativação do Cromossomo X , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
8.
Am J Med Genet A ; 182(7): 1780-1784, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32302040
9.
Hum Mutat ; 40(10): 1731-1748, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31045291

RESUMO

Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3' ends of mitochondrial pre-tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of HCM and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism.


Assuntos
Cardiomiopatia Hipertrófica/genética , Genes Mitocondriais , Predisposição Genética para Doença , Mutação , Proteínas de Neoplasias/genética , Processamento Pós-Transcricional do RNA , RNA de Transferência/genética , Alelos , Substituição de Aminoácidos , Biomarcadores , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/terapia , Estudos de Coortes , Ativação Enzimática , Feminino , Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Cinética , Masculino , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Fenótipo , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-Atividade , Especificidade por Substrato
10.
Am J Med Genet A ; 179(7): 1126-1138, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31058441

RESUMO

CHOPS syndrome is a multisystem disorder caused by missense mutations in AFF4. Previously, we reported three individuals whose primary phenotype included cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, and short stature. This syndrome overlaps phenotypically with Cornelia de Lange syndrome, but presents distinct differences including facial features, pulmonary involvement, and obesity. Here, we provide clinical descriptions of an additional eight individuals with CHOPS syndrome, as well as neurocognitive analysis of three individuals. All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes. All 11 individuals had short stature and obesity. Congenital heart disease and pulmonary involvement were common, and those were seen in about 70% of individuals with CHOPS syndrome. Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density. Our observation indicates that obesity, pulmonary involvement, skeletal findings are the most notable features distinguishing CHOPS syndrome from Cornelia de Lange syndrome. In fact, two out of eight of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing. These phenotypic findings establish CHOPS syndrome as a distinct, clinically recognizable disorder. Additionally, we report three novel missense mutations causative for CHOPS syndrome that lie within the highly conserved, 14 amino acid sequence of the ALF homology domain of the AFF4 gene, emphasizing the critical functional role of this region in human development.


Assuntos
Anormalidades Craniofaciais/genética , Nanismo/genética , Orelha/anormalidades , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Pneumopatias/genética , Mutação de Sentido Incorreto , Pescoço/anormalidades , Obesidade/genética , Tórax/anormalidades , Fatores de Elongação da Transcrição/genética , Adolescente , Sequência de Aminoácidos , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/patologia , Análise Mutacional de DNA , Síndrome de Cornélia de Lange , Diagnóstico Diferencial , Nanismo/diagnóstico , Nanismo/patologia , Orelha/patologia , Fácies , Feminino , Expressão Gênica , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/patologia , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Pneumopatias/diagnóstico , Pneumopatias/patologia , Masculino , Pescoço/patologia , Obesidade/diagnóstico , Obesidade/patologia , Fenótipo , Síndrome , Tórax/patologia , Adulto Jovem
11.
Am J Hum Genet ; 97(2): 302-10, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26166480

RESUMO

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.


Assuntos
Transporte Ativo do Núcleo Celular/genética , Cromossomos Humanos X/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Sequência de Aminoácidos , Sequência de Bases , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Dados de Sequência Molecular , Linhagem , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Análise de Sequência de DNA , Síndrome
12.
Am J Hum Genet ; 97(2): 343-52, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26235985

RESUMO

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.


Assuntos
RNA Helicases DEAD-box/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Caracteres Sexuais , Via de Sinalização Wnt/genética , Substituição de Aminoácidos/genética , Animais , Sequência de Bases , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Exoma/genética , Feminino , Dosagem de Genes/genética , Humanos , Deficiência Intelectual/patologia , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA , Peixe-Zebra
13.
Genet Med ; 20(9): 1061-1068, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29215649

RESUMO

PURPOSE: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. METHODS: A 20-gene panel was designed based on the genes' association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. RESULTS: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre-Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. CONCLUSION: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre-Chotzen syndrome.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Craniossinostoses/genética , Efrina-B1/genética , Austrália , Estudos de Coortes , Suturas Cranianas/patologia , Proteínas de Ligação a DNA/genética , Feminino , Fator 10 de Crescimento de Fibroblastos/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Nova Zelândia , Proteínas Nucleares/genética , Estudos Prospectivos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Repressoras/genética , Estudos Retrospectivos , Fatores de Transcrição/genética , Proteína 1 Relacionada a Twist/genética
14.
Hum Mol Genet ; 24(18): 5250-9, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26123493

RESUMO

Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE; also known as epilepsy and mental retardation limited to females, EFMR; MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression; enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions.


Assuntos
Caderinas/genética , Epilepsia/sangue , Epilepsia/genética , Mutação , Pregnanolona/deficiência , 3-Hidroxiesteroide Desidrogenases/genética , 3-Hidroxiesteroide Desidrogenases/metabolismo , Adolescente , Adulto , Idade de Início , Membro C3 da Família 1 de alfa-Ceto Redutase , Criança , Pré-Escolar , Análise por Conglomerados , Epilepsia/diagnóstico , Feminino , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Hidroxiprostaglandina Desidrogenases/genética , Hidroxiprostaglandina Desidrogenases/metabolismo , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Pessoa de Meia-Idade , Fenótipo , Pregnanolona/sangue , Protocaderinas , Reprodutibilidade dos Testes , Transdução de Sinais , Adulto Jovem
15.
Hum Mol Genet ; 24(7): 2000-10, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25504045

RESUMO

We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.


Assuntos
Proteínas de Transporte/genética , Homozigoto , Doenças do Recém-Nascido/genética , Mutação , Doenças Neurodegenerativas/genética , Proteínas Adaptadoras de Transporte Vesicular , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
16.
Hum Mol Genet ; 24(25): 7171-81, 2015 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-26443594

RESUMO

Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.


Assuntos
Antígenos Nucleares/genética , Deficiência Intelectual/genética , Proteínas de Ciclo Celular , Cromossomos Humanos X/genética , Variações do Número de Cópias de DNA/genética , Humanos , Masculino , Comportamento Problema , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Am J Hum Genet ; 94(3): 470-8, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24607389

RESUMO

With a wealth of disease-associated DNA variants being recently reported, the challenges of providing their functional characterization are mounting. Previously, as part of a large systematic resequencing of the X chromosome in 208 unrelated families with nonsyndromic X-linked intellectual disability, we identified three unique variants (two missense and one protein truncating) in USP9X. To assess the functional significance of these variants, we took advantage of the Usp9x knockout mouse we generated. Loss of Usp9x causes reduction in both axonal growth and neuronal cell migration. Although overexpression of wild-type human USP9X rescued these defects, all three USP9X variants failed to rescue axonal growth, caused reduced USP9X protein localization in axonal growth cones, and (in 2/3 variants) failed to rescue neuronal cell migration. Interestingly, in one of these families, the proband was subsequently identified to have a microdeletion encompassing ARID1B, a known ID gene. Given our findings it is plausible that loss of function of both genes contributes to the individual's phenotype. This case highlights the complexity of the interpretations of genetic findings from genome-wide investigations. We also performed proteomics analysis of neurons from both the wild-type and Usp9x knockout embryos and identified disruption of the cytoskeleton as the main underlying consequence of the loss of Usp9x. Detailed clinical assessment of all three families with USP9X variants identified hypotonia and behavioral and morphological defects as common features in addition to ID. Together our data support involvement of all three USP9X variants in ID in these families and provide likely cellular and molecular mechanisms involved.


Assuntos
Cromossomos Humanos X , Deficiência Intelectual/genética , Mutação , Neurônios/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/fisiologia , Animais , Movimento Celular , Proliferação de Células , Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/genética , Saúde da Família , Feminino , Genes Ligados ao Cromossomo X , Variação Genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Neurogênese/genética , Fenótipo , Fatores de Tempo , Fatores de Transcrição/genética
19.
BMC Med Genet ; 18(1): 52, 2017 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-28482824

RESUMO

BACKGROUND: Cataract is a major cause of severe visual impairment in childhood. The purpose of this study was to determine the genetic cause of syndromic congenital cataract in an Australian mother and son. METHOD: Fifty-one genes associated with congenital cataract were sequenced in the proband using a custom Ampliseq library on the Ion Torrent Personal Genome Machine (PGM). Reads were aligned against the human genome (hg19) and variants were annotated. Variants were prioritised for validation by Sanger sequencing if they were novel, rare or previously reported to be associated with paediatric cataract and were predicted to be protein changing. Variants were assessed for segregation with the phenotype in the affected mother. RESULT: A novel likely pathogenic variant was identified in the transactivation domain of the MAF gene (c.176C > G, p.(Pro59Arg)) in the proband and his affected mother., but was absent in 326 unrelated controls and absent from public variant databases. CONCLUSION: The MAF variant is the likely cause of the congenital cataract, Asperger syndrome, seizures, hearing loss and facial characteristics in the proband, providinga diagnosis of Aymé-Gripp syndrome for the family.


Assuntos
Catarata/congênito , Deficiências do Desenvolvimento/genética , Perda Auditiva/genética , Fatores de Transcrição Maf/genética , Mutação de Sentido Incorreto , Convulsões/genética , Adulto , Sequência de Aminoácidos , Animais , Catarata/genética , Feminino , Humanos , Fatores de Transcrição Maf/química , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Adulto Jovem
20.
J Genet Couns ; 26(1): 159-172, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27443149

RESUMO

The role of genetic counselors in prenatal paternity testing has not been widely studied in the genetic counseling literature. In South Australia, the genetic counselors of the State's public sector clinical genetics service are the primary contact point for women seeking information and testing, also coordinating the testing process. This has provided the opportunity to review all prenatal paternity testing performed in the State over a 13 year period and to consider the role played by the genetic counselor. We explored the reasons why women requested prenatal paternity testing and whether the genetic counselor was an appropriate health professional to facilitate this testing for women. The study had two parts, an audit of the clinical genetics files of 160 women who requested prenatal paternity testing between March 2001 and March 2014, and qualitative interviews of genetic counselors, clinical geneticists, obstetricians and social workers with involvement in this area. The audit determined that in 69.9 % of cases the long-term partner was the father of the pregnancy, for 23.7 % the short-term or other partner was the father and for 6.4 % the paternity results were not known by the genetic counselor. For 45.5 % of women whose long-term partner was excluded as the father, the women chose to have a termination of pregnancy. The results of the qualitative interviews yielded five major themes: accessibility of testing, role of the genetic counselor, social and relationship issues, decision making in pregnancy and emotional issues. We conclude that the genetic counselor is an appropriate health professional to facilitate prenatal paternity testing. Genetic counselors did not view their role as significantly different from a request for prenatal testing for another indication.


Assuntos
Conselheiros , Tomada de Decisões , Aconselhamento Genético , Mães/psicologia , Paternidade , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Austrália do Sul , Adulto Jovem
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