Research
Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10
Abstract
Background. A relatively high frequency of autosomal recessively inherited osteogenesis imperfecta (OI) type 3 (OI-3) is present in the indigenous black southern African population. Affected persons may be severely handicapped as a result of frequent fractures, progressive deformity of the tubular bones and spinal malalignment.
Objective. To delineate the molecular basis for the condition.
Methods. Molecular investigations were performed on 91 affected persons from seven diverse ethnolinguistic groups in this population.
Results. Following polymerase chain reaction amplification and direct cycle sequencing, FKBP10 mutations were identified in 45.1% (41/91) OI-3-affected persons. The homozygous FKBP10 c.831dupC frameshift mutation was confirmed in 35 affected individuals in the study cohort. Haplotype analysis suggests that this mutation is identical among these OI-3-affected persons by descent, thereby confirming that they had a common ancestor. Compound heterozygosity of this founder mutation was observed, in combination with three different deleterious FKBP10 mutations, in six additional persons in the cohort. Four of these individuals had the c.831delC mutation.
Conclusion. The burden of the disorder, both in frequency and severity, warrants the establishment of a dedicated service for molecular diagnostic confirmation and genetic management of persons and families with OI in southern Africa.
Authors' affiliations
Alvera Vorster, MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Department of Pathology, 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, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
Manogari Chetty, Department of Oral and Molecular Biology, Faculty of Dentistry, University of the Western Cape, Cape Town, South Africa
Yasmeen Ganie, Department of Paediatrics and Child Health, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Division of Paediatric Endocrinology, Inkosi Albert Luthuli Central Hospital, Durban, South Africa
Bertram Henderson, Division of Clinical Genetics, Department of Neurology, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa
Engela Honey, Department of Genetics, Faculty of Health Sciences, University of Pretoria, South Africa
Piet Maré, Paediatric Orthopaedic Unit, Department of Orthopaedic Surgery, Grey’s Hospital, Pietermaritzburg, and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
David Thompson, Paediatric Orthopaedic Unit, Department of Orthopaedic Surgery, Grey’s Hospital, Pietermaritzburg, and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
Karen Fieggen, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
Denis Viljoen, Foundation for Alcohol Related Research (FARR), Rondebosch, Cape Town, South Africa
Rajkumar Ramesar, MRC Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa
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Date published: 2017-04-25
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