title: 5alpha-reductase 2 gene mutations in three unrelated patients of Greek Cypriot origin: identification of an ancestral founder effect.
abstract: BACKGROUND
  5alpha-Steroid reductase deficiency (5alphaSRD) is an autosomal recessive enzymatic deficiency. Mutations in the 5alpha-steroid reductase type 2 gene (SRD5A2) result in male pseudohermaphroditism caused by decreased dihydrotestosterone (DHT) synthesis--a key hormone of virilization of male external genitalia.
  
  
  OBJECTIVE
  To study for the first time patients from the Greek Cypriot population, describe their clinical characteristics, and identify the genetic mutations of the SRD5A2 gene.
  
  
  METHODS
  Three unrelated patients with 46,XY karyotype born with ambiguous genitalia were examined. Patient 1 was raised as a girl and was diagnosed with partial androgen insensitivity syndrome, based on the clinical picture and incomplete laboratory investigation at the age of 4 years, and underwent gonadectomy. For this patient sequencing analysis of all five exons of the SRD5A2 gene and exons 2 to 8 of the androgen receptor (AR) gene was performed. Patients 2 and 3 were also born with ambiguous genitalia. The hCG test for these two patients was informative of 5alphaSRD, as it showed elevated T/DHT ratio after stimulation. Despite genetic counseling, both families decided to raise their infants as females because of severe under-virilization. Sequencing of the SRD5A2 gene was also completed for both patients.
  
  
  RESULTS
  No mutations were found in the AR sequence for patient 1. Patients 1 and 3 were found homozygous for the mutation A/G at splice junction intron 1/exon 2 and patient 2 was found heterozygous for the same A/G substitution and also heterozygous for an additional mutation, Pro181Leu, in exon 3.
  
  
  CONCLUSIONS
  The same mutation in the SRD5A2 gene was identified in three unrelated patients, in both homozygous and heterozygous form. This splice mutation was previously reported in Turkish patients. This underlying genetic abnormality may be characteristic for the Eastern Mediterranean region and is likely due to an ancestor effect.
authors.affiliation: Pediatric Endocrine Clinic, Makarios Hospital, Nicosia, Cyprus. nskordis@cytanet.com.cy
authors.forename: Nicos
authors.initials: N
authors.lastname: Skordis
authors.forename: Philippos C
authors.initials: PC
authors.lastname: Patsalis
authors.forename: Ioanna
authors.initials: I
authors.lastname: Bacopoulou
authors.forename: Carolina
authors.initials: C
authors.lastname: Sismani
authors.forename: Charles
authors.initials: C
authors.lastname: Sultan
authors.forename: Serge
authors.initials: S
authors.lastname: Lumbroso
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D000328:Adult; D003535:Cyprus; D004252:DNA Mutational Analysis; D012734:Disorders of Sex Development / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005836:Genitalia, Female / Q000002:abnormalities; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007621:Karyotyping; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics
chemical_list: D022821:RNA Splice Sites; D011944:Receptors, Androgen; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase