Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/126914
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Type: Journal article
Title: Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis
Author: Byrne, A.B.
Mizumoto, S.
Arts, P.
Yap, P.
Feng, J.
Schreiber, A.W.
Babic, M.
King-Smith, S.L.
Barnett, C.P.
Moore, L.
Sugahara, K.
Mutlu-Albayrak, H.
Nishimura, G.
Liebelt, J.E.
Yamada, S.
Savarirayan, R.
Scott, H.S.
Citation: Journal of Medical Genetics, 2020; 57(7):454-460
Publisher: BMJ Publishing Group
Issue Date: 2020
ISSN: 0022-2593
1468-6244
Statement of
Responsibility: 
Alicia B Byrne, Shuji Mizumoto, Peer Arts, Patrick Yap, Jinghua Feng, Andreas W Schreiber, Milena Babic, Sarah L King-Smith, Christopher P Barnett, Lynette Moore, Kazuyuki Sugahara, Hatice Mutlu-Albayrak, Gen Nishimura, Jan E Liebelt, Shuhei Yamada, Ravi Savarirayan, Hamish S Scott
Abstract: 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.
Keywords: Clinical genetics; molecular genetics
Rights: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
RMID: 1000012909
DOI: 10.1136/jmedgenet-2019-106700
Grant ID: http://purl.org/au-research/grants/nhmrc/1123341
http://purl.org/au-research/grants/nhmrc/GNT1113531
http://purl.org/au-research/grants/nhmrc/1023059
Appears in Collections:Medicine publications

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