Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

Byrne A. B., Mizumoto S., Arts P., Yap P., Feng J., Schreiber A. W., ...Daha Fazla

JOURNAL OF MEDICAL GENETICS, cilt.57, sa.7, ss.454-460, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 57 Sayı: 7
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1136/jmedgenet-2019-106700
  • Dergi Adı: JOURNAL OF MEDICAL GENETICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.454-460
  • Anahtar Kelimeler: molecular genetics, clinical genetics, TRANSPORTER DTDST GENE, PROTEIN LINKAGE REGION, DESBUQUOIS DYSPLASIA, DIASTROPHIC DYSPLASIA, SULFATE TRANSPORTER, SKELETAL DYSPLASIA, B3GAT3 MUTATION, CANT1 MUTATION, CLONING, EXPRESSION
  • Ankara Üniversitesi Adresli: Evet

Özet

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) andCANT1(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 theB3GAT3variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstreamin vitrofunctional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of theCANT1variant 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 genesB3GAT3andCANT1, 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.