![]() ![]() The functional TNXB and the TNXA pseudogene are located on the complement strand. Unequal crossover during meiosis generates large structural rearrangements and copy number changes, whereas gene conversion mediates relatively short sequence transfers ( 8).įigure 1 Genomic organization of the CYP21 locus on chromosome 6p21.1-21.3: The functional CYP21A2 gene and its non-functional CYP21A1P pseudogene are arranged in tandem repeat with the two C4 genes that encode factor four of the complement system, the serine–threonine nuclear protein kinase active gene RP1 ( STK19) and a truncated pseudogene RP2 ( STK19P). The genetic diversity of the RCCX module is highly attributable to nonallelic homologous recombination (NAHR). The locus, is one of the most complex in the human genome since it contains three other genes, RP1 also called STK19 that encodes a serine/threonine protein kinase, C4A and C4B that encode two isoforms of complement factor C4, and TNXB that encodes an extracellular matrix glycoprotein tenascin-X (TNX), as well as two pseudogenes, RP2 and TNXA, that together constitute a 30-kb genetic unit called the RCCX module ( 4– 7). The close proximity and high level of homology between the functional and the non-functional gene facilitates misalignment resulting in recombination events that frequently produce large CYP21A2 gene deletions and conversions as well as point pathogenic variants in the CYP21A2 gene. Both the functional gene and the pseudogene comprise ten exons that share a 98% nucleotide sequence identity ( 4– 7). There is a nonfunctional pseudogene (C YP21A1P), located approximately 30 kb from the CYP21A2 gene. The CYP21A2 gene is located on the long arm of chromosome 6, within the major human histocompatibility complex (HLA), a region with a complex gene organization ( 4– 7) ( Figure 1). Prevalence of the most severe or classic forms is 1:16,000 live births in the Caucasian population, while the non-classic or late-onset form is the most common, with a prevalence between 1:1000-1:500 live births depending on ethnicity and geographic area ( 1– 3). ![]() The most common form of CAH is 21-hydroxylase deficiency (21-OHD) accounting for 95% of cases. ![]() Residual enzyme activity defines the clinical severity of the disease. CAH is mostly associated with pathogenic variants in the 21-hydroxylase ( CYP21A2) gene ( 1, 2). Furthermore, clinical features of EDS and clinical recommendations for long-term follow-up are discussed.Ĭongenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive enzymatic disorders, caused by a deficiency of one of the enzymes required for cortisol biosynthesis in the adrenal cortex. In this minireview, we will address the different strategies of molecular analysis of the TNXB-gene, as well as copy number variations and genetic status of TNXB in different cohorts. As molecular analysis of the TNXB gene is challenging, the TNX-deficient type EDS is probably underdiagnosed. EDS comprises a clinically and genetically heterogeneous group of connective tissue disorders. TNXB deficiency is associated with Ehlers Danlos syndrome (EDS). Three TNXA/TNXB chimeras have been described that differ in the junction site (CH1 to CH3) and result in a contiguous CYP21A2 and TNXB gene deletion, causing CAH-X syndrome. Chimeric recombination may occur between TNXB and TNXA. During meiosis, misalignment may occur producing large gene deletions or gene conversion events resulting in chimeric genes. TNX plays a role in collagen deposition by dermal fibroblasts and is expressed in the dermis of the skin and the connective tissue of the heart and skeletal muscle. Other duplicated genes are C4A and C4B, that encode two isoforms of complement factor C4, the RP1 gene that encodes a serine/threonine protein kinase, and the TNXB gene that, encodes the extracellular matrix glycoprotein tenascin-X (TNX). This locus also contains the CYP21A1P, a non-functional pseudogene, that is highly homologous to the CYP21A2 gene. The 21-hydroxylase enzyme P450c21 is encoded by the CYP21A2 gene located on chromosome 6p21.33 within the HLA major histocompatibility complex.
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