Aberrant splicing of the CHM gene is a significant cause of choroideremia

Abstract

Choroideremia (CHM) is an X-linked progressive degeneration of the choroid and retina. 12% of unrelated male patients carry deletions of the partially cloned CHM gene. In Finland, there are more than 120 living CHM patients belonging to eight apparently unrelated pedigrees. Molecular deletions involving the CHM gene have been detected in three families. We have screened the remaining five families for point mutations. In one large family a single nucleotide (T) insertion into the donor splice site of exon C leads to two aberrantly spliced mRNAs both producing a premature stop codon. The mutation can be assayed easily by amplification and digestion with Msel. Our findings provide additional evidence for the pathogenetic role of CHM mutations and provide a diagnostic tool for one fifth of the world's known CHM patients.

Altered mRNA Expression due to Insertion or Substitution of Thymine at Position +3 of Two Splice-Donor Sites in the Androgen Receptor Gene

“…Splice-donor site +3 mutations have been incriminated as the cause of human genetic disease in 14 other cases [6-17 and references therein]. Of the total, 3 are+3 A>T [8,12,17],as in our subject 4479, and 4 are +3insT [6,9,11,14], as in our subject 926203. The phenotypic consequence of the AR Intl(+3insT) or the Int6(+3A > T) mutation is complete androgen insensitivity.…”

“…The critical nature of the +3 splicedonor site position in normal mRNA processing is high lighted by the identification of 14 other +3 splice-donor site mutations in a variety of human genetic diseases [6][7][8][9][10][11][12][13][14][15][16][17], and references to +3 mutations therein].…”

Positional Cloning of Disease Genes: Advantages of Genetic Isolates

“…Out of some 33 diseases, the chromosomal locus is known for 17, and the mutated gene identified for 15, (AGU, 208400) aspartylglucosaminidase [Ikonen et al, 1991] Choroideremia (303100) Rab geranylgeranyl transferase [Sankila et al, 1992] Congenital chloride diarrhea (CCD, 214700) chloride transporter [Höglund et al, 1996] Congenital nephrosis (CNF, 256300) nephrin ] Diastrophic dysplasia (DTD, 222600) sulfate transporter [Hästbacka et al, 1994b] Familial amyloidosis, Finnish type (FAF, 105120) gelsolin [Levy et al, 1990] Gyrate atrophy of choroid & retina (HOGA, 258870) ornithine Á-aminotransferase [Mitchell et al, 1989] Hypergonadotrophic ovarial dysgenesis (233300) follicle-stimulating hormone receptor [Aittomäki et al, 1995] Infantile neuronal ceroid lipofuscinosis (INCL, 256730) palmitoyl protein thioesterase [Vesa et al, 1995] Lysinuric protein intolerance (LPI, 222700) L-amino acid transporter [Lauteala et al, 1997] Nonketotic hyperglycinemia (NKH, 238300) glycine cleavage system; protein P [Kure et al, 1992 (600334) 2q [Haravuori et al, 1998] Usher syndrome, type III (276902) 3q most of them by positional cloning (table 1). According to expectations, all these disorders have shown extreme locus and allelic homogeneity.…”

A 3-base pair insertional mutation in the choroideremia gene

“…In studies of European families with CHM, a total of 15 different mutations have been reported Sankila et al, 1992;Schwartz et al, 1993;Donnelly et al, 1994;van Bokhoven et al, 1994b) in the CHM gene. All the mutations, except one, result in the formation of a stop codon at the site of the mutation or create frameshift mutations that lead to premature stop codons.…”