RESUMO
BACKGROUND: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive disorder caused by pathogenic variants of the conserved telomere maintenance component 1 (CTC1) gene. The CTC1 forms the telomeric capping complex, CST, which functions in telomere homeostasis and replication. METHODS: A Brazilian pedigree and an Australian pedigree were referred to the International Registry of Werner Syndrome (Seattle, WA, USA), with clinical features of accelerated aging and recurrent bone fractures. Whole exome sequencing was performed to identify the genetic causes. RESULTS: Whole exome sequencing of the Brazilian pedigree revealed compound heterozygous pathogenic variants in CTC1: a missense mutation (c.2959C>T, p.Arg987Trp) and a novel stop codon change (c.322C>T, p.Arg108*). The Australian patient carried two novel heterozygous CTC1 variants, c.2916G>T, p.Val972Gly and c.2926G>T, p.Val976Phe within the same allele. Both heterozygous variants were inherited from the unaffected father, excluding the diagnosis of CRMCC in this pedigree. Cell biological studies demonstrated accumulation of double strand break foci in lymphoblastoid cell lines derived from the patients. Increased DSB foci were extended to non-telomeric regions of the genome, in agreement with previous biochemical studies showing a preferential binding of CTC1 protein to GC-rich sequences. CONCLUSION: CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. Further studies are needed to elucidate the disease mechanism leading to the clinical presentation with intra-familial variations of CRMCC.
Assuntos
Fraturas Ósseas/genética , Mutação , Fenótipo , Proteínas de Ligação a Telômeros/genética , Síndrome de Werner/genética , Adulto , Linhagem Celular , Quebras de DNA de Cadeia Dupla , Feminino , Fraturas Ósseas/patologia , Sequência Rica em GC , Instabilidade Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Ligação Proteica , Telômero/genética , Proteínas de Ligação a Telômeros/metabolismo , Síndrome de Werner/patologiaRESUMO
Congenital generalized lipodystrophy (CGL) is a genetically heterogeneous group of disorders characterized by the absence of functional adipose tissue. We identified two pedigrees with CGL in the community of the Mestizo tribe in the northern region of Peru. Five cases, ranging from 15 months to 7 years of age, presented with generalized lipodystrophy, muscular prominence, mild intellectual disability, and a striking aged appearance. Sequencing of the BSCL2 gene, known to be mutated in type 2 CGL (CGL2; Berardinelli-Seip syndrome), revealed a homozygous deletion of exon 3 in all five patients examined, suggesting the presence of a founder mutation. This intragenic deletion appeared to be mediated by recombination between Alu sequences in introns 2 and 3. CGL2 in this population is likely underdiagnosed and undertreated because of its geographical, socio-economic, and cultural isolation.© 2016 Wiley Periodicals, Inc.
Assuntos
Subunidades gama da Proteína de Ligação ao GTP/genética , Lipodistrofia Generalizada Congênita/diagnóstico , Lipodistrofia Generalizada Congênita/genética , Mutação , Fenótipo , Recombinação Genética , Sequência de Bases , Criança , Pré-Escolar , Consanguinidade , Éxons , Fácies , Feminino , Efeito Fundador , Estudos de Associação Genética , Humanos , Incidência , Lactente , Masculino , Linhagem , PeruRESUMO
We previously found that single nucleotide polymorphisms in the low-density lipoprotein receptor-related protein 6 (LRP6) gene are associated with Alzheimer's disease (AD). Here, we studied the posttranscriptional metabolism of the LRP6 message scanning sequentially the 23 LRP6 exons in human tissues and found a novel LRP6 isoform that completely skips exon 3 (LRP6Δ3) in all tissues examined and was also conserved in mice. Expression levels of the LRP6 isoforms were determined in 47 cortical brain messenger (m)RNA samples including 22 AD cases, 11 control subjects, and 14 individuals with other neurological disorders. LRP6Δ3 mRNA levels were significantly augmented in AD brains compared with controls (1.6-fold; p = 0.037) or other pathological samples (2-fold; p = 0.007). Functional analysis in Wnt/ß-catenin signaling assays revealed that skipping of exon 3 reduced significantly the signaling activity of the LRP6 coreceptor. We conclude that the LRP6Δ3 isoform is a novel splice variant, which shows diminished Wnt/ß-catenin signaling activity and might have a functional role in individuals with AD.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Estudos de Associação Genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Isoformas de Proteínas/genética , Via de Sinalização Wnt/genética , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo/genética , Animais , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
The American Journal of Public Health (English)