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1.
Am J Med Genet A ; 188(8): 2360-2366, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35751429

RESUMO

Joubert syndrome (JS), a well-established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. Exome sequencing detected a de novo heterozygous missense variant in SLC30A7: NM_133496.5: c.407 T > C, (p.Val136Ala). The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. A de novo deletion-insertion variant in SLC30A7, c.490_491delinsAG (p.His164Ser) was found. Both de novo variants affect highly conserved residues. Variants were not identified in known Joubert genes for either case. SLC30A7 has not yet been associated with a human phenotype. The SLC30 family of zinc transporters, like SLC30A7, permit cellular efflux of zinc, and although it is expressed in the brain its functions remain unknown. Published data from proteomic studies support SLC30A7 interaction with TCTN3, another protein associated with JS. The potential involvement of such genes in primary cilia suggest a role in Sonic Hedgehog signaling. SLC30A7 is a candidate JS-associated gene. Future work could be directed toward further characterization of SLC30A7 variants and understanding its function.


Assuntos
Anormalidades Múltiplas , Proteínas de Transporte de Cátions/genética , Anormalidades do Olho , Doenças Renais Císticas , Megalencefalia , Polidactilia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Ataxia , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Proteínas Hedgehog , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Proteômica , Retina/anormalidades , Zinco
2.
Eur J Med Genet ; 60(10): 504-508, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28687524

RESUMO

We present a 7-year old male with severe delays, hypotonia and dysmorphic features who had striking, deep palmar and plantar creases and pillowing of the soft tissues of the palms and soles. His facial features included a high anterior hairline, small eyes with narrowed palpebral fissures, a bulbous nasal tip with a short columella, and a large mouth with a thin upper vermilion, and small chin. He had a submucous cleft palate, bilateral cryptorchidism and hydronephrosis. Cranial imaging demonstrated an Arnold Chiari malformation that was also present in his maternal uncle by report. Exome sequencing revealed a de novo heterozygous sequence variant, p.Tyr446Cys, in TBL1XR1 that has previously been reported in six patients with Pierpont syndrome. This sequence variant occurs in the carboxy-terminal, WD40 domain of the protein. As TBL1XR1 is a critical component of the NCoR/SMRT co-repressor complex and the WD40 repeats are hypothesized to interact with histone H2B and H4, the mutation may impact protein interactions necessary for stabilizing the complex with chromatin. De novo missense and frameshift mutations and deletions involving TBL1XR1 have been described in patients with intellectual disability and autism, but without any of the dysmorphic findings or malformations associated with Pierpont syndrome, implying a mutation-specific mechanism for the pathogenicity of p.Tyr446Cys. Our case is the first individual with this mutation to have a submucous cleft palate and hydronephrosis, although his severe delays, hypotonia, dysmorphic findings and emerging scoliosis appear consistent with previous reports. His distinctive facial and digital features are further evidence that p.Tyr446Cys results in a clinically recognizable, syndromic form of intellectual disability in contrast to other TBL1XR1 mutations.


Assuntos
Malformação de Arnold-Chiari/genética , Deficiências do Desenvolvimento/genética , Hipotonia Muscular/genética , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Malformação de Arnold-Chiari/diagnóstico , Criança , Deficiências do Desenvolvimento/diagnóstico , Humanos , Masculino , Hipotonia Muscular/diagnóstico , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Fenótipo , Ligação Proteica , Domínios Proteicos , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Síndrome
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