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Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10

Alvera Vorster, Peter Beighton, Manogari Chetty, Yasmeen Ganie, Bertram Henderson, Engela Honey, Piet Maré, David Thompson, Karen Fieggen, Denis Viljoen, Rajkumar Ramesar

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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Keywords

Africa; Bruck syndrome; Fractures, FKBP10; Genetic; Osteogenesis imperfecta; Skeletal

Cite this article

South African Medical Journal 2017;107(5):457-462. DOI:10.7196/SAMJ.2017.v107i5.9461

Article History

Date submitted: 2017-04-25
Date published: 2017-04-25

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