Insertion of a T next to the donor splice site of intron 1 causes aberrantly spliced mRNA in a case of infantile GM1-gangliosidosis.
The lysosomal storage disorders GM1-gangliosidosis and Morquio B syndrome are caused by a complete or partial deficiency of acid beta-galactosidase. Here, we have characterized the mutation segregating in a family with two siblings affected by the severe infantile form of GM1-gangliosidosis. In total mRNA preparations derived from the patients' fibroblasts at least two aberrantly spliced beta-galactosidase transcripts (1 and 2) have been identified. Both transcripts contain a 20 nucleotide (nt) insertion derived from the 5' end of intron 1 of the beta-galactosidase gene. Furthermore, in transcript 2 sequences encoded by exon II are deleted during the splicing process. Comparison of the 20-nt insertion with wild-type intronic sequences indicated that in the genomic DNA of the patients an extra T nucleotide is present immediately downstream of the conserved GT splice donor dinucleotide of intron 1. Both patients are homozygous for the T nucleotide insertion. We propose that this single base insertion is the mutation responsible for aberrant splicing of beta-galactosidase pre-mRNA, giving rise to transcripts that cannot encode a normal protein.
Morrone
A
A
Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
Morreau
H
H
Zhou
X Y
XY
Zammarchi
E
E
Kleijer
W J
WJ
Galjaard
H
H
d'Azzo
A
A
D001483:Base Sequence; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis / Q000235:genetics; D005347:Fibroblasts; D016537:Gangliosidosis, GM1 / Q000235:genetics*; D005796:Genes; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011296:Prenatal Diagnosis; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics
D012333:RNA, Messenger