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1.
Artigo em Inglês | MEDLINE | ID: mdl-31736240

RESUMO

The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.

4.
Nat Commun ; 9(1): 4619, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30397230

RESUMO

Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.

5.
Clin Epigenetics ; 10(1): 95, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30005706

RESUMO

BACKGROUND: Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes. RESULTS: In this study, we used oocyte-specific Zp3-Cre recombinase (Zp3Cre) to delete Eed specifically in mouse growing oocytes, permitting the study of EED function in oocytes and the impact of depleting EED in oocytes on outcomes in offspring. As EED deletion occurred only in growing oocytes and females were mated to normal wild type males, this model allowed the study of oocyte programming without confounding factors such as altered in utero environment. Loss of EED from growing oocytes resulted in a significant overgrowth phenotype that persisted into adult life. Significantly, this involved increased adiposity (total fat) and bone mineral density in offspring. Similar overgrowth occurs in humans with Cohen-Gibson (OMIM 617561) and Weaver (OMIM 277590) syndromes, that result from de novo germline mutations in EED or its co-factor EZH2, respectively. Consistent with a role for EZH2 in human oocytes, we demonstrate that de novo germline mutations in EZH2 occurred in the maternal germline in some cases of Weaver syndrome. However, deletion of Ezh2 in mouse oocytes resulted in a distinct phenotype compared to that resulting from oocyte-specific deletion of Eed. CONCLUSIONS: This study provides novel evidence that altering EED-dependent oocyte programming leads to compromised offspring growth and development in the next generation.

7.
Hum Mutat ; 37(3): 301-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26694085

RESUMO

Weaver syndrome (WS) is a rare congenital disorder characterized by generalized overgrowth, macrocephaly, specific facial features, accelerated bone age, intellectual disability, and susceptibility to cancers. De novo mutations in the enhancer of zeste homolog 2 (EZH2) have been shown to cause WS. EZH2 is a histone methyltransferase that acts as the catalytic agent of the polycomb-repressive complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating histone methyltransferase activity of mutant EZH2 from various cancers have been reported, whereas WS-associated mutations remain poorly characterized. To investigate the role of EZH2 in WS, we performed functional studies using artificially assembled PRC2 complexes containing mutagenized human EZH2 that reflected the codon changes predicted from patients with WS. We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay. Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2. However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2.


Assuntos
Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/enzimologia , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/enzimologia , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Deformidades Congênitas da Mão/enzimologia , Deformidades Congênitas da Mão/genética , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Feminino , Histona Metiltransferases , Humanos , Lactente , Recém-Nascido , Masculino , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo
8.
J Hum Genet ; 60(6): 339-42, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25787343

RESUMO

In a patient suspected clinically to have Weaver syndrome, we ruled out mutations in EZH2 and NSD1, then identified a previously undescribed de novo mutation in EZH2's partner protein EED. Both proteins are members of the Polycomb Repressive Complex 2 that maintains gene silencing. On the basis of the similarities of the patient's phenotype to Weaver syndrome, which is caused by de novo mutations in EZH2, and on other lines of evidence including mouse Eed hypomorphs, we characterize this mutation as probably pathogenic for a Weaver-like overgrowth syndrome. This is the first report of overgrowth and related phenotypes associated with a constitutional mutation in human EED.


Assuntos
Anormalidades Múltiplas/diagnóstico , Hipotireoidismo Congênito/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Transtornos do Crescimento/diagnóstico , Deformidades Congênitas da Mão/diagnóstico , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/genética , Adulto , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Humanos , Masculino , Mutação de Sentido Incorreto
9.
J Pediatr Endocrinol Metab ; 28(3-4): 345-51, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25720052

RESUMO

BACKGROUND: Inheritance of two pathogenic ABCC8 alleles typically causes severe congenital hyperinsulinism. We describe a girl and her father, both homozygous for the same ABCC8 mutation, who presented with unusual phenotypes. METHODS: Single nucleotide polymorphism microarray and Sanger sequencing were performed. Western blot, rubidium efflux, and patch clamp recordings interrogated the expression and activity of the mutant protein. RESULTS: A 16-month-old girl of consanguineous descent manifested hypoglycemia. She had dysregulation of insulin secretion, with postprandial hyperglycemia followed by hypoglycemia. Microarray revealed homozygosity for the regions encompassing KCNJ11 and ABCC8. Her father had developed diabetes at 28 years of age. Sequencing of ABCC8 identified a homozygous missense mutation, p.R1419H, in both individuals. Functional studies showed absence of working KATP channels. CONCLUSION: This is the first description of a homozygous p.R1419H mutation. Our findings highlight that homozygous loss-of-function mutations of ABCC8 do not necessarily translate into early-onset severe hyperinsulinemia.


Assuntos
Hiperglicemia/genética , Hipoglicemia/genética , Receptores Sulfonilureia/genética , Adulto , Substituição de Aminoácidos , Arginina/genética , Células Cultivadas , Consanguinidade , Família , Feminino , Histidina/genética , Homozigoto , Humanos , Hiperglicemia/complicações , Hiperglicemia/patologia , Hipoglicemia/complicações , Hipoglicemia/patologia , Lactente , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo
10.
Am J Med Genet A ; 164A(9): 2360-4, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24903541

RESUMO

We describe a patient who presented with a localized growth of mature fat tissue, which was surgically removed. MRI imaging identified diffuse increase in visceral adipose tissue. Targeted deep sequencing of the resected tissue uncovered a p.H1047R variant in PIK3CA, which was absent in blood. This report expands the phenotypic spectrum of mosaic PIK3CA mutations.


Assuntos
Lipomatose/enzimologia , Lipomatose/genética , Mesentério/patologia , Mosaicismo , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Polimorfismo de Nucleotídeo Único/genética , Tecido Adiposo/patologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Humanos , Lactente
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