Twin genes and endocrine disease: CYP21 and CYP11B genes

Helmberg, Arno

doi:10.1530/acta.0.1290097

Cited by 21 publications

(19 citation statements)

References 56 publications

(99 reference statements)

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“…This high level of sequence homology and co-localization together with potential recombination hot spots (Alu repeats, Chi sequence and human minisatellites repeats) may result in the functional gene becoming susceptible to recombination events such as gene conversion or crossing over among the functional gene and pseudogenes . Gene conversion events between homologous genes and their pseudogenes have been described in the pathogenesis of several genetic disorders, such as 21-hydroxylase deficiency (Helmberg 1993), von Willebrand disease (Eikenboom et al 1994) and Gaucher disease (Horowitz et al 1989). Among the 12 patients from the 11 unrelated families, homozygosity mapping showed that CGD in four patients is linked to NCF1, with all of these patients having the NCF1 DGT deletion.…”

Section: Discussionmentioning

confidence: 99%

Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia

et al. 2006

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NADPH oxidase, a multi-subunit protein consisting of cytosolic components and the membranebound heterodimer,plays an instrumental role in host defence mechanisms of phagocytes. Genetic deficiency of the enzymatic complex results in an inherited disorder, chronic granulomatous disease (CGD), which is characterized by an impaired phagocyte microbicidal activity. X-Linked (XL) CGD results from a mutation in the CYBB gene encoding the gp91phox subunit, while autosomal recessive (AR) CGD is associated with mutations in one of the NCF1, NCF2 and CYBA genes that encode the p47phox, p67phox and p22phox subunits, respectively. In the study reported here, we investigated genetic defects underlying CGD in 15 Tunisian patients from 14 unrelated families. Haplotype analyses and homozygosity mapping with microsatellite markers around known CGD genes assigned the genetic defect to NCF1 in four patients, to NCF2 in four patients and to CYBA in two patients. However, one family with two CGD patients seemed not to link the genetic defect to any known AR-CGD genes. Mutation screening identified two novel mutations in NCF2 and CYBA in addition to the recurrent mutation, DGT, in NCF1 and a splice site mutation previously reported in a North African patient. Our results revealed the genetic and mutational heterogeneity of the AR recessive form of CGD in Tunisia.

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Section: Discussionmentioning

confidence: 99%

Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia

et al. 2006

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“…The overall degree of divergence (exons plus introns) from the wild-type clones was found to be in the range 0.4% to 0.8%, thus rendering the p47-phox pseudogenes among the most conserved unprocessed pseudogenes known. Examples of other highly homologous unprocessed pseudogenes are the 21-hydroxylase pseudogene (CYP21A) (98% homology in exons and 96% homology in introns) (40), the von Willebrand factor pseudogene (96.9% overall homology) (41) and the ␤-glucocerebrosidase pseudogene (96% overall homology) (42).…”

Section: Discussionmentioning

confidence: 99%

“…As the products of crossing over and gene conversion events are virtually indistinguishable at the DNA level in higher eukaryotes, however, such events are commonly referred to as gene conversions (45). Gene conversion events between homologous genes and their pseudogenes have been described in the pathogenesis of several genetic disorders such as 21-hydroxylase deficiency (40), von Willebrand disease (46), and Gaucher disease (42), and have also been postulated for many clustered gene families (47). The presence of at least one p47-phox pseudogene carrying the GT deletion suggests that such events might also be responsible for the transfer of the GT deletion from the p47-phox pseudogene to the wild-type gene, thus leading to A47Њ CGD.…”

Section: Discussionmentioning

confidence: 99%

“…In the 21-hydroxylase pseudogene, for example, an 8-bp deletion, a single-bp insertion and a nonsense mutation (as well as six additional mutations) notably cause loss of the function of the wild-type protein when transferred to the wild-type gene. Each of these deleterious mutations accounts for a proportion of 21-hydroxylase-deficient patients (40). Out of the nine single base pair substitutions identified in the coding region of the p47-phox pseudogene, however, only three (R→H, S→G, D→N, Table III) predict amino acid changes.…”

Section: Discussionmentioning

confidence: 99%

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A p47-phox pseudogene carries the most common mutation causing p47-phox- deficient chronic granulomatous disease.

Görlach¹,

Lee²,

Roesler³

et al. 1997

J. Clin. Invest.

125

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The predominant genetic defect causing p47-phox -deficient chronic granulomatous disease (A47 Њ CGD) is a GT deletion ( ⌬ GT) at the beginning of exon 2. No explanation exists to account for the high incidence of this single mutation causing a rare disease in an unrelated, racially diverse population. In each of 34 consecutive unrelated normal individuals, both the normal and mutant ⌬ GT sequences were present in genomic DNA, suggesting that a p47-phox related sequence carrying ⌬ GT exists in the normal population. Screening of genomic bacteriophage and YAC libraries identified 13 p47-phox bacteriophage and 19 YAC clones. The GT deletion was found in 11 bacteriophage and 15 YAC clones. Only 5 exonic and 33 intronic differences distinguished all ⌬ GT clones from all wild-type clones. The most striking differences were a 30-bp deletion in intron 1 and a 20-bp duplication in intron 2. These results provide good evidence for the existence of at least one highly homologous p47-phox pseudogene containing the ⌬ GT mutation.

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“…So, further investigation must be done for differential diagnosis of LOCAH due to 21-OH deficiency. Recently, the clinical presentations and molecular genetics of late onset 21-hydroxylase deficiency have been reviewed in considerable detail in the Ashkenazi Jewish, Hispanic, Italian, Yugoslav and American populations [1,3,[8][9][10][11]. The most common mutation is V281L (exon 7, codon 281), and it is present in 59.0% of the patients.…”

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confidence: 99%

The Prevalence, Molecular Analysis and HLA Typing of Late-onset 21-Hydroxylase Deficiency in Turkish Woman with Hirsutism and Polycystic Ovary

et al. 2004

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Abstract. We studied the incidence of late-onset congenital adrenal hyperplasia (LOCAH) due to 2l-hydroxylase (21-OH) deficiency, its molecular genotype expression, and its association with the major histocompatibility complex in 61 women with hirsutism and polycystic ovary. Ultrasound, clinical and hormonal parameters were used to define polycystic ovary syndrome (PCOS). Baseline and ACTH stimulated 17a-hydroxyprogesterone (17-OHP) levels were measured for screening of LOCAH during follicular phase. Forty-one women were diagnosed as having PCOS (67%) and 20 women were diagnosed as having had LOCAH due to 2l-OH deficiency (33%). In LOCAH patients, the most common mutation (Val281-Leu, V281L) was found in 10 patients (7 heterozygous/3 homozygous). The frequency of V281L mutation was found as 32.5% in 20 patients. All patients with the V281L mutation presented HLA-B14 (100%) and six of them presented DR1 (60%), confirming that LOCAH is linked to the histocompatibility complex. Although molecular analysis is a better and more accurate means for an exact and precise definition of LOCAH, it is not routinely available in our country. So, ACTH stimulation test combined with HLA-B14 typing should be more widely utilized in these patients. As a result, LOCAH due to 21-OH deficiency is unexpectedly high in Turkish patients with hirsutism and PCO.

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Twin genes and endocrine disease: CYP21 and CYP11B genes

Cited by 21 publications

References 56 publications

Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia

Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia

A p47-phox pseudogene carries the most common mutation causing p47-phox- deficient chronic granulomatous disease.

The Prevalence, Molecular Analysis and HLA Typing of Late-onset 21-Hydroxylase Deficiency in Turkish Woman with Hirsutism and Polycystic Ovary

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