Molecular study of the 5 alpha-reductase type 2 gene in three European families with 5 alpha-reductase deficiency.

Abstract

The molecular basis of 5 alpha-reductase (5 alpha R) deficiency was investigated in four patients from three European families. In the French family, the first patient was raised as a female, and gonadectomy was performed before puberty. The second sibling, also raised as female, differed in that gonadal removal was performed after the onset of pubertal masculinization. The other two patients, both from Polish families, developed masculinization of external genitalia during puberty. All patients developed a female sexual identity. In all cases, no known consanguinity or family history of 5 alpha R deficiency was reported. The genomic DNAs of the patients were sequenced after polymerase chain reaction amplification of the five exons of the 5 alpha R type 2 gene. We found two homozygous mutations responsible for glutamine to arginine and histidine to arginine substitution in families 1 and 3, respectively. In family 2, we found a heterozygous mutation responsible for an asparagine to serine substitution at position 193. The glutamine/arginine 126 mutation in the French family was previously reported in a Creole ethnic group, and the Polish histidine/arginine 231 mutation was previously reported in a patient from Chicago. Moreover, all of the mutations created new restriction sites, which were used to determine the kindred carrier status in the three families. Because 5 alpha R deficiency is known to be a heterogenous disease in terms of clinical and biochemical expression, our data suggest that molecular biology analysis of the type 2 gene could be an essential step in diagnosing 5 alpha R deficiency.

Primary amenorrhea in four adolescents revealed 5α-reductase deficiency confirmed by molecular analysis

“…These patients exhibited micropenis and hypospadias and were reared as girls at birth, but they switched to male sex at puberty (13-14 years old), in contrast to our patient (17). p.N193S was also observed in a 16-year-old Polish patient who exhibited clitoral enlargement and virilization (7), and in a 17-year-old patient of Mexican-Mestizo origin with micropenis and perineoscrotal hypospadias without cryptorchidism (24). Patient 4 was found to carry compound heterozygous mutations (p.R246W/c.34delG).…”

“…Our group and others have described a wide spectrum of clinical phenotypes in patients with an alteration in the 5a-reductase enzyme (5)(6)(7)(8). The spectrum ranges from minimal masculinization of the external genitalia presenting with isolated micropenis (9) or hypospadias to severe undervirilization appearing as normal female external genitalia with mild clitoral enlargement (5)(6)(7)(8).…”

“…The spectrum ranges from minimal masculinization of the external genitalia presenting with isolated micropenis (9) or hypospadias to severe undervirilization appearing as normal female external genitalia with mild clitoral enlargement (5)(6)(7)(8).…”

Phenotype, Sex of Rearing, Gender Re-Assignment, and Response to Medical Treatment in Extended Family Members with a Novel Mutation in the SRD5A2 Gene

“…In 2 related patients diagnosed with SRD5A2 deficiency in the Highlands of Papua New Guinea, deletion of most of the SRD5A2 gene was detected (21). In addition, Boudon et al (22) reported a trinucleotide deletion straddling codons 156 and 157, responsible for a methionine residue deletion at position 157 of the protein in a Turkish patient. Mutations in exon 2 have been reported.…”

Contribution of the Endocrine Perspective in the Evaluation of Endocrine Disrupting Chemical Effects: The Case Study of Pubertal Timing

“…That enzyme transforms testosterone into the potent androgen dihydrotestosterone, which is needed for normal prenatal masculinization. The genitals of these under-masculinized boys, however, become sensitive to testosterone with age, and virilization develops at puberty [62]. Individual (genetic) differences in sensitivity of some endpoints are also to be considered, such as those due to ethnic or racial variations: the differences in the development of pubic hair appear to be much more important than the differences in the increase in testicular volume [3], again pointing to the importance of endpoints and study conditions.…”