Title

Molecular analysis of six factor xiii-a-deficient families in Southern Pakistan

Document Type

Article

Department

Haematology/Oncology; Pathology and Microbiology

Abstract

Factor XIII deficiency is a severe autosomal recessive bleeding disorder which is commonly due to absence of the A subunit protein. Molecular studies have shown that factor XIII-A deficiency is genetically heterogeneous and over 40 mutations have been described in the A subunit gene. We have recently performed genetic analysis on six apparently unrelated families with inherited factor XIII-A deficiency from the Southern region of Pakistan. In five families, affected individuals were shown to have an identical homozygous splice site mutation – a single nucleotide substitution (G→A) of the last base of exon 14. This mutation, which has been previously described in two Caucasian patients in the UK, results in exon skipping of exon 14 and a truncated mRNA transcript ( Anwar et al, 1995 ). Further analysis using the HUMF13A01 short tandem repeat (STR) marker closely linked to the A subunit gene ( Polymeropoulos et al, 1991 ) showed that 9 of the 10 alleles with the exon 14 G→A mutation were associated with an identical (AAAG)5 repeat. The level of consanguinity in the Pakistan population is high and this observation would suggest a founder effect (i.e. inheritance of a common ancestral gene mutation). One patient, however, was heterozygous for the (AAAG)5 allele and an (AAAG)7 repeat. As microsatellite instability is apparently rare in STR sequences with repeat numbers of < 10 and almost invariably involves loss or gain of a single repeat ( Brinkmann et al, 1998 ), it seems likely that the two identical exon 14 splice site mutations in this patient have arisen independently.

Publication

British Journal of Haematology