Research

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia

Christopher Mark Watson, Laura A Crinnion, Lindsay Gleghorn, William G Newman, Rajkumar Ramesar, Peter Beighton, Gillian A Wallis

Abstract


Background. Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35.

Objective. To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing.

Results. The linked BHD allele was refined to 1.33 Mb, reducing the number of candidate genes from 25 to 16. Analysis of protein coding and invariant splice-site sequences in three distantly related individuals identified a single-candidate disease-causing variant c.868T>C within exon 8 of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 gene, UFSP2. The presence of this unique mutation was confirmed in all 17 affected members of the BHD family who were genotyped. The mutation segregated with the BHD phenotype in the extended family with a two-point (single marker) LOD score of 10.4 (θ = 0.0 and 80% penetrance). The mutation predicts the substitution of a highly conserved amino acid, p.Tyr290His, in the encoded protein. In vitro functional assays performed using purified recombinant wild-type and mutant UFSP2 protein demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, Ufm1.

Conclusion. We report a unique UFSP2 mutation that segregates with the BHD phenotype. The predicted amino acid substitution inactivates UFSP2 proteolytic function, thus implicating the ubiquitin-fold modifier 1 cascade in this form of severe hip osteoarthropathy. The facile polymerase chain reaction-based assay we describe could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family. 


Authors' affiliations

Christopher Mark Watson, Yorkshire Regional Genetics Service and School of Medicine, University of Leeds, St James’s University Hospital, Leeds, UK

Laura A Crinnion, Yorkshire Regional Genetics Service and School of Medicine, University of Leeds, St James’s University Hospital, Leeds, UK

Lindsay Gleghorn, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK

William G Newman, Centre for Genomic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

Rajkumar Ramesar, MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa

Peter Beighton, MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa

Gillian A Wallis, Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK

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Keywords

Beukes hip dysplasia; UFSP2; Ufm1 cascade; Exome sequencing

Cite this article

South African Medical Journal 2015;105(7):558-563. DOI:10.7196/SAMJnew.7917

Article History

Date submitted: 2014-12-24
Date published: 2015-09-21

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