Close Genetic Linkage Between Hla and Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Dupont, Bo; Oberfield, Sharon E.; Smithwick, Elizabeth M.; Lee, T.D; Levine, Lenore S.

doi:10.1016/s0140-6736(77)90362-2

Cited by 356 publications

(93 citation statements)

References 5 publications

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“…The active gene, CYP21, is 98% homologous to the pseudo gene, CYP21P, which is non-functional due to several mutations (4,5). Both genes are located within the HLA class III region on chromosome 6p21.3 and form two C4/CYP21 units with adjacent complement C4A and C4B genes (6). High sequence identity and close proximity of the two genes facilitate gene recombination and gene conversion events in this region, resulting in gene deletions, duplications or large gene conversions (7).…”

Section: Introductionmentioning

confidence: 99%

Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease

Dolžan

Stopar-Obreza²,

Žerjav-Tanšek³

et al. 2003

European Journal of Endocrinology

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Objective: To analyse the mutational spectrum, the associated haplotypes and the genotype -phenotype correlation, and to design a reliable and rational approach for CYP21 mutation detection in Slovenian congenital adrenal hyperplasia (CAH) patients. Design: Molecular analysis of the CYP21 gene was performed in 36 CAH patients and 79 family members. Methods: Southern blotting, sequence-specific PCR amplification (PCR-SSP), sequence-specific oligonucleotide hybridisation (PCR-SSO) and sequencing were used to detect CYP21 gene deletions, conversions and point mutations. Results: CYP21 gene deletion was the most frequent mutation (36.4%). Large gene conversions detectable only by Southern blotting represented 12.1%, and gene conversions involving the promoter region represented 7.6% of the mutated alleles. The most frequent point mutations were: intron 2 splice mutation 16.7%, Ile172Asn mutation 7.6%, Gln318Stop 7.5% and Pro30Leu 12.2% of alleles. A correlation between the genotype and the clinical phenotype similar to those described for large populations was observed. The finding of Pro30Leu mutation linked to a gene conversion could explain the simple virilising (SV) phenotype in compound heterozygotes for the Pro30Leu and a severe mutation. In two siblings with a salt wasting form of CAH (SW-CAH), a novel mutation Ala15Thr was found on the allele characterised by Pro30Leu mutation and gene conversion involving the promoter region. Conclusions: Our genotyping approach allowed reliable diagnosis of CAH in the Slovenian population. The high frequency of CYP21 gene aberrations on Pro30Leu positive alleles justified systematic searching for a gene conversion in the promoter region using the PCR-SSP reaction.

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Section: Introductionmentioning

confidence: 99%

Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease

Dolžan

Stopar-Obreza²,

Žerjav-Tanšek³

et al. 2003

European Journal of Endocrinology

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“…CYP21 genes located in the central region of the major histocompatibility complex (MHC) on chromosome 6 are in close genetic linkage with human leucocyte antigens (HLA) (14). Characteristic HLA haplotypes are associated with CAH, but this association differs among populations.…”

Section: Introductionmentioning

confidence: 99%

Adrenal 21-hydroxylase gene mutations in Slovenian hyperandrogenic women: evaluation of corticotrophin stimulation and HLA polymorphisms in screening for carrier status

Dolžan¹,

Preželj²,

Vidan-Jeras³

et al. 1999

European Journal of Endocrinology

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Objective: To study the incidence of 21-hydroxylase deficiency in Slovenian hyperandrogenic women, at the gene level. Previous endocrine studies indicated large differences in the incidence of 21-hydroxylase deficiency in hyperandrogenic women. The predictive values of the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation and of HLA typing in screening for carrier status were re-evaluated. Design: Molecular analysis of CYP21 gene, ACTH stimulation and human leucocyte antigen (HLA) typing were performed in 83 consecutive Slovenian hyperandrogenic women. Measurements: Cortisol and 17-OHP concentrations were measured at baseline and 60 min after ACTH stimulation. Basal adrenal androgen concentrations were also measured. Results: None of 83 hyperandrogenic patients was affected with non-classical 21-hydroxylase deficiency, but 12 of 81 patients (14.8%) had high concentrations of 17-OHP after stimulation, indicative of carrier status. The increase in 17-OHP concentrations could be explained by a carrier status for CYP21 gene mutations in only three of 12 patients (25%), whereas seven of 69 patients (10.1%) with normal concentrations of 17-OHP after stimulation were found to be carriers of CYP21 gene mutations, indicating low positive predictive values of ACTH stimulation as a screening test for carriers of 21-hydroxylase deficiency. In total, 11 carriers were identified among 83 patients: seven CYP21 gene deletions/conversions, two Gln

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“…6 Linkagebased diagnostic methods have been reported using various markers in the MHC. HLA serotyping 7 provided a mechanism to track mutant alleles within families but could not be easily applied to prenatal samples obtained by amniocentesis.…”

Section: Linkagementioning

confidence: 99%

An Overview of Molecular Diagnosis of Steroid 21-Hydroxylase Deficiency

Keegan

Killeen

2001

The Journal of Molecular Diagnostics

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Close Genetic Linkage Between Hla and Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)

Cited by 356 publications

References 5 publications

Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease

Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease

Adrenal 21-hydroxylase gene mutations in Slovenian hyperandrogenic women: evaluation of corticotrophin stimulation and HLA polymorphisms in screening for carrier status

An Overview of Molecular Diagnosis of Steroid 21-Hydroxylase Deficiency

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