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Titolo:
FUNCTIONAL-CHARACTERIZATION OF THE NOVEL L108W AND P186L MUTATIONS DETECTED IN THE TYPE-II 3-BETA-HYDROXYSTEROID DEHYDROGENASE GENE OF A MALE PSEUDOHERMAPHRODITE WITH CONGENITAL ADRENAL-HYPERPLASIA
Autore:
SANCHEZ R; MEBARKI F; RHEAUME E; LAFLAMME N; FOREST MG; BEYOMARD F; DAVID M; MOREL Y; LABRIE F; SIMARD J;
Indirizzi:
CHU LAVAL,RES CTR,MRC,MOLEC ENDOCRINOL GRP,2705 LAURIER BLVD QUEBEC CITY G1V 4G2 PQ CANADA CHU LAVAL,RES CTR,MRC,MOLEC ENDOCRINOL GRP QUEBEC CITY G1V 4G2 PQ CANADA UNIV LAVAL QUEBEC CITY G1V 4G2 PQ CANADA UNIV LYON,DEPT PEDIAT LYON 05 FRANCE HOP DEBROUSSE LYON 05 FRANCE
Titolo Testata:
Human molecular genetics
fascicolo: 9, volume: 3, anno: 1994,
pagine: 1639 - 1645
SICI:
0964-6906(1994)3:9<1639:FOTNLA>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
TISSUE-SPECIFIC EXPRESSION; DELTA-5-DELTA-4 ISOMERASE; PERIPHERAL-TISSUES; 3-BETA-HSD GENE; DEFICIENCY; FAMILY; VIRUS; LIVER; INHIBITION; DEFECT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
45
Recensione:
Indirizzi per estratti:
Citazione:
R. Sanchez et al., "FUNCTIONAL-CHARACTERIZATION OF THE NOVEL L108W AND P186L MUTATIONS DETECTED IN THE TYPE-II 3-BETA-HYDROXYSTEROID DEHYDROGENASE GENE OF A MALE PSEUDOHERMAPHRODITE WITH CONGENITAL ADRENAL-HYPERPLASIA", Human molecular genetics, 3(9), 1994, pp. 1639-1645

Abstract

Two isoenzymes are responsible for 3 beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3 beta-HSD) activity in humans. We analyzed the structure of types I and II 3 beta-HSD genes in a male pseudohermaphrodite suffering from a severe salt-losing form of congenital adrenal hyperplasia. We did not detect any mutation in the type I 3 beta-HSD gene, but we found two different missense mutations in exon IV of the type II 3 beta-HSD gene of the patient; a conversion of codon Leu(108) into a Trp (L108W) inherited from his mother and a conversion of codon Pro(186) into a Leu (P186L) inherited from his father. We assessed the effect of the L108W and P186L mutations on 3 beta-HSD activity by in vitro analysis of mutant enzymes expressed in heterologous COS-1 cells. Using homogenates from transfected cells, the K-m values forPREG were 7 +/- 2 and 8 +/- 2 mu M for the recombinant L108W and P186L enzymes, respectively, compared with 2.2 +/- 0.2 mu M for the normaltype II 3 beta-HSD enzyme. Moreover, K-m values for NAD(+) were much higher for the L108W and P186L proteins, being 678 +/- 166 and 920 +/-361 mu M, respectively, compared with 24 +/- 3 mu M for the normal type II BP-HSD enzyme. V-max values for PREG and NAD(+) were lower for both mutant enzymes; thus, the in vitro overall efficiency, relative tothe normal enzyme, is approximate as 0.3% and 0.2% for the L108W and P186L enzymes, respectively. The present study is the first description of mutations which significantly affect the affinity for NAD(+) in addition to reducing the affinity for PREG, thus providing useful information on the structure-activity relationships of the 3 beta-HSD enzyme superfamily. Moreover, this patient is the first case presenting thesalt-wasting form of classical 3 beta-HSD deficiency caused by mutated alleles possessing residual enzymatic activity. The combination of decreased K-m values for the steroid substrate and cofactor thus explains the severe form of this enzymatic defect responsible for congenitaladrenal hyperplasia and male pseudohermaphroditism.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 18:51:57