title: Aberrant splicing and missense mutations cause steroid 21-hydroxylase [P-450(C21)] deficiency in humans: possible gene conversion products.
abstract: Four steroid 21-hydroxylase B [P-450(C21)B] genes (designated P.7, P.10-1, P.10-2, and P.3) from three P-450(C21)-deficient patients were isolated to analyze their structures and functions. Several base changes were observed in the sequences of the four P-450(C21)B genes as compared to that of the functional B gene. Many of these base changes were identical to those of the P-450(C21)A pseudogene. The three DNAs (P.10-1, P.10-2, and P.3) produced no P-450(C21) activity in a functional assay for P-450(C21) by the COS cell expression system, while the P.7 DNA expressed the activity. The P.10-1 and P.10-2 DNAs were shown to have a point mutation in the second intron, causing aberrant splicing. The P.3 DNA carried three clustered missense mutations in the sixth exon, which impaired P-450(C21) activity. All these critical mutations could be seen in the corresponding site of the P-450(C21)A pseudogene. These data strongly suggest the involvement of gene conversion in this genetic disease.
authors.affiliation: Department of Biochemistry, Cancer Institute, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Higashi
authors.forename: A
authors.initials: A
authors.lastname: Tanae
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Hiromasa
authors.forename: Y
authors.initials: Y
authors.lastname: Fujii-Kuriyama
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics*; D004720:Endonucleases; D005091:Exons; D005785:Gene Conversion; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D009154:Mutation; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D015719:Single-Strand Specific DNA and RNA Endonucleases; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D004247:DNA; D013250:Steroid Hydroxylases; D013255:Steroid 21-Hydroxylase; D004720:Endonucleases; D015719:Single-Strand Specific DNA and RNA Endonucleases