INVESTIGADORES
BERGADÁ Ignacio
artículos
Título:
Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia.
Autor/es:
MARINO R; RAMIREZ P; GALEANO J; PEREZ GARRIDO N; ROCCO C ; CIACCIO M ; WARMAN DM; GUERCIO G; CHALER E; MACEIRAS M; BERGADÁ I; GRYNGARTEN M; BALBI V; PARDES E; RIVAROLA MA; BELGOROSKY A
Revista:
CLINICAL ENDOCRINOLOGY
Editorial:
WILEY-BLACKWELL PUBLISHING, INC
Referencias:
Lugar: Londres; Año: 2011 vol. 75 p. 427 - 435
ISSN:
0300-0664
Resumen:
Objective To report genotype?phenotype correlation in a large
cohort of patients.
Context Study of the CYP21A2 gene in 866 unrelated chromosomes
of 21-hydroxylase deficiency in Argentinean patients with
classic and nonclassic (NC) forms of congenital adrenal hyperplasia
(CAH).
Methods Eleven most common mutations were analysed by
allele-specific polymerase chain reaction, restriction fragment
length polymorphism (RFLP) or southern blot analysis. Gene
sequencing was performed when no mutation was detected in one
allele or the genotype?phenotype correlation was lacking.
Results The 11-most-common-mutation screening allowed for
the detection of 88Æ1% of affected alleles (80Æ3% in the NC and
95Æ2% in the classic forms). p.V281L, IVS2-13A/C>G (In2) and
gene deletions and large gene conversions were the most prevalent
mutations. In2 (35Æ2%) in salt wasting (SW), p.I172N (37Æ3%) in
simple virilizing and p.V281L (54Æ1%) in NC CAH were the most
prevalent mutations within the clinical forms. In 7/15 p.P30L
mutation alleles, a chimeric CYP21A1P/CYP21A2 gene [Prom-
CYP21A1P; p.P30L] was detected, while 6/15 represented a singlenucleotide
substitution, and in 2/15 linkage with mutations,
p.[P30L; V281L] and [p.P30L; IVS2-13A/C > G; p.Q318X] was
found. In two SW patients, a novel nonsense mutation, p.Q41X,
was observed. In three p.V281L mutation patients, the phenotype
was more severe than predicted by genotype. Sequence analysis
revealed an intronic alteration in the allele carrying the p.V281L
mutation [IVS2 + 5G > A; p.V281L]. An aberrant splicing in this
p.V281L mutated allele explains the clinical phenotype.
Conclusions A high percentage of CYP21A2 affected alleles is
detected by the 11-mutation screening study. Genotype?phenotype
correlation was high, but when the phenotype is more severe than
predicted by genotype, presence of two alterations in one allele
should be ruled out.