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Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC-related disorder.
Sage, Adam P; Lee, Hyun Kyung; Dalmann, Joshua; Lin, Susan; Samra, Simran; Salman, Areesha; Del Bel, Kate L; Li, Wenhui Laura; Lehman, Anna; Turvey, Stuart E; Boerkoel, Cornelius F; Richmond, Phillip A.
Afiliación
  • Sage AP; MD Undergraduate Program, University of British Columbia, Vancouver, British Columbia, Canada.
  • Lee HK; Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Dalmann J; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Lin S; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Samra S; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Salman A; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Del Bel KL; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Li WL; Breakthrough Genomics, Irvine, California, USA.
  • Lehman A; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Turvey SE; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Boerkoel CF; Department of Medical Genetics and Provincial Medical Genetics Program, University of British Columbia and Women's Hospital of British Columbia, Vancouver, British Columbia, Canada.
  • Richmond PA; The Rare Disease Discovery Hub, BC Children's Hospital Research Institute, University of British Columbia and Children's Hospital of British Columbia, Vancouver, British Columbia, Canada.
Am J Med Genet A ; 191(8): 2219-2224, 2023 08.
Article en En | MEDLINE | ID: mdl-37196051
Tandem splice acceptors (NAGNn AG) are a common mechanism of alternative splicing, but variants that are likely to generate or to disrupt tandem splice sites have rarely been reported as disease causing. We identify a pathogenic intron 23 CLTC variant (NM_004859.4:c.[3766-13_3766-5del];[=]) in a propositus with intellectual disability and behavioral problems. By RNAseq analysis of peripheral blood mRNA, this variant generates transcripts using cryptic proximal splice acceptors (NM_004859.4: r.3765_3766insTTCACAGAAAGGAACTAG, and NM_004859.4:r.3765_3766insAAAGGAACTAG). Given that the propositus expresses 38% the level of CLTC transcripts as unaffected controls, these variant transcripts, which encode premature termination codons, likely undergo nonsense mediated mRNA decay (NMD). This is the first functional evidence for CLTC haploinsufficiency as a cause of CLTC-related disorder and the first evidence that the generation of tandem alternative splice sites causes CLTC-related disorder. We suggest that variants creating tandem alternative splice sites are an underreported disease mechanism and that transcriptome-level analysis should be routinely pursued to define the pathogenicity of such variants.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Sitios de Empalme de ARN / Haploinsuficiencia Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Med Genet A Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Canadá
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Sitios de Empalme de ARN / Haploinsuficiencia Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Am J Med Genet A Asunto de la revista: GENETICA MEDICA Año: 2023 Tipo del documento: Article País de afiliación: Canadá