Genes and Pseudogenes: Complexity of the RCCX Locus and Disease.

Cinzia Carrozza,Laura Foca,Paola Concolino,Elisa De Paolis

doi:10.3389/fendo.2021.709758

Cinzia Carrozza, Laura Foca + Show 2 more

Open Access

https://doi.org/10.3389/fendo.2021.709758

Copy DOI

Abstract

Copy Number Variations (CNVs) account for a large proportion of human genome and are a primary contributor to human phenotypic variation, in addition to being the molecular basis of a wide spectrum of disease. Multiallelic CNVs represent a considerable fraction of large CNVs and are strictly related to segmental duplications according to their prevalent duplicate alleles. RCCX CNV is a complex, multiallelic and tandem CNV located in the major histocompatibility complex (MHC) class III region. RCCX structure is typically defined by the copy number of a DNA segment containing a series of genes – the serine/threonine kinase 19 (STK19), the complement 4 (C4), the steroid 21-hydroxylase (CYP21), and the tenascin-X (TNX) – lie close to each other. In the Caucasian population, the most common RCCX haplotype (69%) consists of two segments containing the genes STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB, with a telomere-to-centromere orientation. Nonallelic homologous recombination (NAHR) plays a key role into the RCCX genetic diversity: unequal crossover facilitates large structural rearrangements and copy number changes, whereas gene conversion mediates relatively short sequence transfers. The results of these events increased the RCCX genetic diversity and are responsible of specific human diseases. This review provides an overview on RCCX complexity pointing out the molecular bases of Congenital Adrenal Hyperplasia (CAH) due to CYP21A2 deficiency, CAH-X Syndrome and disorders related to CNV of complement component C4.

Highlights

Germline Copy Number Variation (CNV) is regarded as a particular DNA fragment with variable copies compared to a reference genome and primarily includes genome duplications and deletions [1]
In this Review, we focus on the genetic complexity of the RCCX CNV discussing the molecular bases of related human diseases as Congenital Adrenal Hyperplasia (CAH)
The challenging related to the molecular diagnosis of 21-hydroxylase deficiency, owed to the complexity of the RCCX CNV structure, are well documented

Summary

INTRODUCTION

Germline Copy Number Variation (CNV) is regarded as a particular DNA fragment with variable copies compared to a reference genome and primarily includes genome duplications and deletions [1]. CNVs account for a large proportion of human genome [2], greatly influence cellular phenotypes such as gene expression [3], and are accountable for a plethora of diseases, in addition to representing relevant disease risk factors [4, 5] These observations raise the possibility that CNVs could be a primary contributor to human phenotypic variation and evolve under selective pressures [5]. CNVs alleles with large, homologous, and tandem repeats are susceptible to rearrangements via NAHR mechanism [8] such as unequal crossover [9] and gene conversion [10] In this Review, we focus on the genetic complexity of the RCCX CNV discussing the molecular bases of related human diseases as Congenital Adrenal Hyperplasia (CAH)

RCCX CNV

Findings

DISCUSSION