Editing 5α-Reductase 2 deficiency (section)

==Genetics==

Two different genes, each with five exons and four introns, designated as SRD5A1 and SDR5A2, encode two different 5α-reductases. The human 5α-reductase-2 gene (SRD5A2) is located on the short arm of chromosome 2 at band 23 and encodes a 254 amino acid protein, called 5α-reductase type 2. The 5α-reductase-1 gene (SRD5A1) is located in band 15 on the short arm of chromosome 5 and encodes a 259 amino acid protein, called 5α-reductase type 1. The high amino acid sequence identity of their proteins (approximately 60%) indicates the possibility of a common precursor gene during evolution. But the role of 5α-reductase type 1 is not well defined.<ref name="Mendonca2016"/>

Mutations in the [[SRD5A2]] gene can result in a [[Disorders of sex development|46,XY disorder of sex development]](46,XY DSD) called 5α-reductase-2 deficiency. These mutations are more often observed in areas with a specific ethnic background and high coefficients of inbreeding. They generate proteins with various degrees of enzymatic activity ranging from an unstable isoenzyme to complete loss of enzymatic activity. Of the 254 amino acids in the 5a-reductase type 2 protein, mutations in codons specifying 67 different residues have been identified, with multiple mutations in the codons of several amino acids <ref name="Mendonca2016"/> 

The first known mutation SRD5A2 was almost a complete [[deletion (genetics)|deletion]] that was discovered from an analysis of affected individuals in a Papua New Guinean tribe.<ref>{{cite journal |last1=Andersson |first1=Stefan |last2=Berman |first2=David M. |last3=Jenkins |first3=Elizabeth P. |last4=Russell |first4=David W. |title=Deletion of steroid 5α-reductase 2 gene in male pseudohermaphroditism |journal=Nature |date=November 1991 |volume=354 |issue=6349 |pages=159–161 |doi=10.1038/354159a0|pmid=1944596 |pmc=4451825 |bibcode=1991Natur.354..159A }}</ref> The majority of SRD5A2 mutations are [[missense mutation]]s, but small deletions, [[Splice site mutation|splice junction mutations]], and gross deletions were also observed.<ref name="Batista2020"/> Mutations result in a spectrum of activity effects ranging from destabilizing 5αR2 to complete loss of activity.<ref name="Mendonca2016"/>

SRD5A2 mutations are inherited in an autosomal recessive pattern. Homozygous defects are more common than compound heterozygous ones. A phenotype-genotype correlation is not known to exist for many of the most common mutations, and affected individuals with the same 5αR2 mutations have variable phenotypes suggesting other interacting genetic factors that determine phenotype.<ref>{{cite journal |last1=Avendaño |first1=Andrea |last2=Paradisi |first2=Irene |last3=Cammarata-Scalisi |first3=Francisco |last4=Callea |first4=Michele |title=5-α-Reductase type 2 deficiency: is there a genotype–phenotype correlation? A review |journal=Hormones |date=June 2018 |volume=17 |issue=2 |pages=197–204 |doi=10.1007/s42000-018-0013-9|pmid=29858846 |doi-access=free }}</ref>