Chimeric Genes Causing 11 β-Hydroxylase Deficiency: Implications in Clinical and Molecular Diagnosis

AbstractDeficiency of 11 β-hydroxylase (11β-OHD) is the second most common cause of congenital adrenal hyperplasia (CAH), accounting for 0.2–8% of all cases. The disease is transmitted as an autosomal recessive trait and the underlying genetic causes of 11β-OHD are primarily small pathogenic variants affecting theCYP11B1 gene coding the 11 β-hydroxylase enzyme. However, special events complicate the molecular diagnosis of 11β-OHD such as an unequal crossing over between theCYP11B2 (coding aldosterone synthase enzyme) andCYP11B1 genes. The resulting allele contains a hybrid gene, with aCYP11B2 5 ′-end and aCYP11B1 3 ′-end, where theCYP11B1 gene is under the control of theCYP11B2 promoter and thus not responding to the adrenocorticotropin (ACTH) but to angiotensin II and K+. This leads a reduction of cortisol production in 11 β-OHD. In particular,CYP11B2/CYP11B1 chimeric genes can be distinguished into two groups depending on the breakpoint site: chimeras with breakpoint after the exon 5 ofCYP11B2 preserve the aldosterone synthase activity, the others with breakpoint before exon 5 lose this function. In the last case, a more severe phenotype is expected. The aim of this review was to explore the setting ofCYP11B2/CYP11B1 chimeras in 11 β-OHD, performing a careful review of clinical literature cases.
Source: Molecular Diagnosis and Therapy - Category: Molecular Biology Source Type: research