Gene conversion (655G splicing mutation) and the founder effect (Gln318Stop) contribute to the most frequent severe point mutations in congenital adrenal hyperplasia (21‐hydroxylase deficiency) in the Spanish population

• Published in: Clinical genetics 2002-08, Vol.62 (2), p.181-188
• Main Authors: Ezquieta, B, Cueva, E, Oyarzábal, M, Oliver, A, Varela, J M, Jariego, C
• Format: Article
• Language: English
• Subjects: 655G intron 2 splicing mutation; Adrenal Hyperplasia, Congenital - genetics; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Biological and medical sciences; Endocrinopathies; Female; Founder Effect; Gene Conversion; Genetic Markers; Gln318Stop mutation; Humans; Male; Medical sciences; Microsatellite Repeats; microsatellite typing; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Spain - epidemiology; Steroid 21-Hydroxylase - genetics; steroid 21‐hydroxylase deficiency
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1034/j.1399-0004.2002.620213.x

This study addresses the contributions of gene conversion and a founder effect to the distribution of the two most frequent severe point mutations of the 21‐hydroxylase (21OH) gene causing congenital adrenal hyperplasia: the 655G splicing mutation at intron 2, and Gln318Stop in a Spanish population. Direct and indirect analyses of segregated mutant and normal 21OH genes in 200 Spanish families (classic and nonclassic 21OH deficiency) were performed. Both mechanisms were found to contribute to different degrees to the defective investigated alleles. The 655G splicing mutation (62 alleles, 15.5%) seemed to be almost exclusively related to recent conversion events, whereas Gln318Stop (33 alleles, 8.3%) is more likely to be due to the dissemination of remotely generated mutant alleles. Other severe defective alleles, 8 bp‐deletion (13 alleles, 3.3%), 306insT (5 alleles, 1.3%), and gene deletions (43 alleles, 11%), as well as the mild mutation Val281Leu (120 alleles, 30%), also appear to be strongly associated with particular D6S273 alleles. Although gene conversion contributes to the generation of severe 21OH alleles, the high frequency of some severe mutations in different geographic areas is consistent with a founder effect.