Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families

Sinnott, Paul J.; Costigan, Colm; Dyer, Philip A.; Harris, Rodney; Strachan, Tom

doi:10.1007/bf00200920

Cited by 13 publications

(9 citation statements)

References 28 publications

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“…Haplotype G1 has two CYP21A2 genes and no CYP21A1P genes and is the same as haplotype 10 in the report of Haglund-Stengler et al (1991); it has also been mentioned by Sinnott et al (1991). We here demonstrate that one of the CYP21A2 genes on such chromosomes has two contiguous mutations (I172N and I236N-V237E-M239K), and that not all haplotypes G1 are the same.…”

Section: Discussionmentioning

confidence: 49%

Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes

2002

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Steroid 21-hydroxylase deficiency, the primary cause of congenital adrenal hyperplasia, is caused by defects of the CYP21A2 gene. As a complement to hormonal measurements, mutation analysis of CYP21A2 is an important tool in the diagnosis of steroid 21-hydroxylase deficiency. Contemporary mutation-detection protocols based on the polymerase chain reaction often depend on the assumption that no more than one CYP21A2 gene is present on each chromosome 6. We describe three haplotypes with two CYP21A2 genes on the same chromosome, with defects typical of salt-losing steroid 21-hydroxylase deficiency in one of those genes, but not necessarily in the other. The frequency of these haplotypes in the general population is 6/365 (1.6%), so they are no less common than other haplotypes that indeed carry steroid 21-hydroxylase deficiency. Chromosomes that carry two CYP21A2 genes therefore represent a significant pitfall in the molecular diagnosis of steroid 21-hydroxylase deficiency. We recommend that, whenever CYP21A2 mutation analysis of an individual who is not a known carrier of steroid 21-hydroxylase deficiency is performed, the overall structure of the CYP21/ C4 region (the RCCX area) is determined by haplotyping to avoid erroneous assignment of carrier status.

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Section: Discussionmentioning

confidence: 49%

Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes

2002

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“…As an example, alleles with one CYP21A2 gene carrying the severe Q318X mutation and a second, normal CYP21A2 gene in the same chromosome, thought to be rare in previous studies [Sinnott et al, 1991;Wedell et al, 1994b;Koppens et al, 2002], were instead reported with a 7% frequency in a recent paper [Parajes et al, 2008] and have also been recently observed in our patients (data in press) using the MLPA technique. Therefore, whenever a Q318X mutation is found, the possibility of the presence of a normal CYP21A2 gene must be taken into account.…”

Section: Complications In the Genetic Counselling Of 21-hydroxylase Dmentioning

confidence: 83%

Impact of Molecular Genetics on Congenital Adrenal Hyperplasia Management

Balsamo

Baldazzi

Menabò

et al. 2010

Sex Dev

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Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations in genes encoding the enzymes involved in one of the 5 steps of adrenal steroid synthesis or the electron donor P450 oxidoreductase (POR) enzyme. Steroid 21-hydroxylase deficiency (21-OHD), the principal focus of this review, accounts for about 90–95% of all CAH cases, and its biochemical and clinical severity depends on the underlying CYP21A2 gene disruption. Molecular genetic advancements have been achieved in recent years, and the aim of this review is to attempt to highlight its contribution to the comprehension and management of the disease. When possible, we will try to achieve this goal also by providing some results from our personal experience regarding: some aspects of CYP21A2 gene analysis, with basic genotype/phenotype relationships; its crucial role in both genetic counselling and in prenatal diagnosis and treatment in families at risk for 21-OHD; its help in the comprehension of the severity of the disease in patients diagnosed by neonatal screening and possibly treated before an evident salt-loss crisis or before performing adequate blood sampling; its usefulness in the definition of post ACTH 17-hydroxyprogesterone values, discriminating between non-classic, heterozygote and normal subjects; and finally the contribution of genes other than CYP21A2 whose function or dysfunction could influence 21-hydroxylase activity and modify the presentation or management of the disease.

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“…Moreover, archaeological findings in these areas are continuous and similar to those found in southern Scandinavia and in the areas east of the Baltic Sea. 1,22 As the identical B40 S30 DR1 haplotype is also consistently found in patients in many other populations in Europe, 10 for example its frequency in Irish patients is 26%, 25 this mutation was probably introduced into the Finnish population by immigration and began to spread nearly 2000 years ago. The fact that we found no consanguinity between any families is in line with this haplotype's believed ancient origin.…”

Section: Cyp21 Mutations and Migrationsmentioning

confidence: 91%

Tracing past population migrations: genealogy of steroid 21-hydroxylase (CYP21) gene mutations in Finland

et al. 1999

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The genealogic origin of steroid 21-hydroxylase gene (CYP21) mutations and associated haplotypes was determined in 74 unrelated Finnish families with CYP21 deficiency (congenital adrenal hyperplasia, CAH). These families account for two thirds (85/119) of all diagnosed patients of Finnish descent found in this country. We recently demonstrated that multiple founder mutations each associated with a particular haplotype can be found in Finland. Interestingly, some of the haplotypes were identical to those observed in various European populations, whereas others have not been described elsewhere, indicating a local and perhaps a more recent origin. In the present report we show that each of the major founder haplotypes originates from a particular geographic region of Finland. Thus many local genetic isolates are to be expected in Finland. Our finding is in a clear contrast to the genetic diseases known as the 'Finnish disease heritage', in which only one mutation usually predominates. Some of the CYP21 haplotypes proved very informative for analysis of the history of the Finnish population. For example, the origin of one frequent haplotype was shown to cluster in a region assumed by archaeological data to be a major site of immigration by settlers of either Scandinavian or Baltic origin during the first centuries AD. As this haplotype is frequent in many European patient populations, we provide independent genetic evidence of this Iron Age immigration. On the other hand, another frequent haplotype found solely in Finland reflects a more recent (post 15th century) settlement expansion. Consequently, well characterised and sufficiently frequent autosomal gene markers can provide useful information on migrations both between and within populations.

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Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families

Cited by 13 publications

References 28 publications

Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes

Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes

Impact of Molecular Genetics on Congenital Adrenal Hyperplasia Management

Tracing past population migrations: genealogy of steroid 21-hydroxylase (CYP21) gene mutations in Finland

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