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High variability in CYP21A2 mutated alleles in Spanish 21‐hydroxylase deficiency patients, six novel mutations and a founder effect
Author(s) -
Loidi Lourdes,
Quinteiro Celsa,
Parajes Silvia,
Barreiro Jesús,
Lestón Domingo G.,
CabezasAgrícola José M.,
Sueiro Aurelio M.,
AraujoVilar David,
CatroFeijóo Lidia,
Costas Javier,
Pombo Manuel,
Domínguez Fernando
Publication year - 2006
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2006.02465.x
Subject(s) - genetics , haplotype , allele , biology , founder effect , point mutation , exon , mutation , allele frequency , gene , microbiology and biotechnology
Summary Objective To detect common as well as rare and novel CYP21A mutations in 21‐hydroxylase deficiency patients. To estimate the distribution of mutations and compare them with other European studies. To construct haplotypes linked to a recurrent novel mutation. Design Genetic analysis by sequencing the entire CYP21A2 gene plus Southern blot. Patients A total of 138 unrelated Spanish patients: 122 nonclassical forms (NCF) and 16 classical forms (CF) were studied. Results Among the 266 nonrelated mutated alleles; CYP21A2 deletions/conversions and a spectrum of 27 different mutated alleles were found: 15 different single point mutations, 8 nucleotide deletions in exon 3, 3 mutation clusters in exon 6, 9 alleles with more than one mutation, one 21‐nucleotide duplication in exon 10, and one allele with CYP21A2 duplicated and both copies mutated. The most frequent mutation in NCF alleles is V281L (71·8%). Among CFs, the most common is I2 g (20%) and Q318X (16%) and rare alleles (21·9%). Six novel causative mutations were found, four associated with CF: I46+1nt, R444X, P463L and M473_R479dup and two associated with NCF: W302 and D322G. The R444X mutation was found in seven unrelated patients and it appeared only once in an ancestral haplotype. In addition, we found a novel single nucleotide polymorphism with a 31·5% frequency for the rare allele. Conclusion A great diversity of haplotypes with a large spectrum of mutated alleles was found. The frequency of the V281L mutation was the highest reported and the relatively high frequency of R444X was the result of a founder effect.