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Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis.
Byrne, Alicia B; Mizumoto, Shuji; Arts, Peer; Yap, Patrick; Feng, Jinghua; Schreiber, Andreas W; Babic, Milena; King-Smith, Sarah L; Barnett, Christopher P; Moore, Lynette; Sugahara, Kazuyuki; Mutlu-Albayrak, Hatice; Nishimura, Gen; Liebelt, Jan E; Yamada, Shuhei; Savarirayan, Ravi; Scott, Hamish S.
Afiliação
  • Byrne AB; Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
  • Mizumoto S; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
  • Arts P; Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
  • Yap P; Research Center for Pathogenesis of Intractable Diseases, Meijo University, Nagoya, Japan.
  • Feng J; Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
  • Schreiber AW; Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
  • Babic M; Victorian Clinical Genetics Service, Royal Children's Hospital, Melbourne, Victoria, Australia.
  • King-Smith SL; Genetic Health Service New Zealand (Northern Hub), Auckland, New Zealand.
  • Barnett CP; Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
  • Moore L; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
  • Sugahara K; ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
  • Mutlu-Albayrak H; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
  • Nishimura G; ACRF Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
  • Liebelt JE; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
  • Yamada S; Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
  • Savarirayan R; Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, South Australia, Australia.
  • Scott HS; Australian Genomics Health Alliance, Melbourne, Victoria, Australia.
J Med Genet ; 57(7): 454-460, 2020 07.
Article em En | MEDLINE | ID: mdl-31988067
BACKGROUND: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. METHODS: Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. RESULTS: WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. CONCLUSION: For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glucuronosiltransferase / Nanismo / Cardiopatias Congênitas / Hérnia Umbilical / Nucleotidases Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male / Pregnancy Idioma: En Revista: J Med Genet Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Austrália

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Glucuronosiltransferase / Nanismo / Cardiopatias Congênitas / Hérnia Umbilical / Nucleotidases Tipo de estudo: Prognostic_studies Limite: Female / Humans / Male / Pregnancy Idioma: En Revista: J Med Genet Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Austrália