Null mutations and lethal congenital form of glycogen storage disease type IV.
Glycogen branching enzyme deficiency (glycogen storage disease type IV, GSD-IV) is a rare autosomal recessive disorder of the glycogen synthesis with high mortality. Two female newborns showed severe hypotonia at birth and both died of cardiorespiratory failure, at 4 and 12 weeks, respectively. In both patients, muscle biopsies showed deposits of PAS-positive diastase-resistant material and biochemical analysis in cultured fibroblasts showed markedly reduced glycogen branching enzyme activity. Direct sequencing of GBE1 gene revealed that patient 1 was homozygous for a novel c.691+5 g>c in intron 5 (IVS5+5 g>c). RT-PCR analysis of GBE1 transcripts from fibroblasts cDNA showed that this mutation produce aberrant splicing. Patient 2 was homozygous for a novel c.1643G>A mutation leading to a stop at codon 548 in exon 13 (p.W548X). These data underscore that in GSD-IV a severe phenotype correlates with null mutations, and indicate that RNA analysis is necessary to characterize functional consequences of intronic mutations.
Muscular and Neurodegenerative Disease Unit, Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Largo G. Gaslini 5, I-16147 Genova, Italy.
Stefania
S
Assereto
Otto P
OP
van Diggelen
Luisa
L
Diogo
Eva
E
Morava
Denise
D
Cassandrini
Isabel
I
Carreira
Willem-Pieter
WP
de Boode
Jildau
J
Dilling
Paula
P
Garcia
Margarida
M
Henriques
Olinda
O
Rebelo
Henk
H
ter Laak
Carlo
C
Minetti
Claudio
C
Bruno
D015061:1,4-alpha-Glucan Branching Enzyme / Q000737:chemistry / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D001706:Biopsy; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D005091:Exons / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006011:Glycogen Storage Disease Type IV / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation / Q000235:genetics*
D018076:DNA, Complementary; D015061:1,4-alpha-Glucan Branching Enzyme