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.
Assereto
Stefania
S
Muscular and Neurodegenerative Disease Unit, Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Largo G. Gaslini 5, I-16147 Genova, Italy.
van Diggelen
Otto P
OP
Diogo
Luisa
L
Morava
Eva
E
Cassandrini
Denise
D
Carreira
Isabel
I
de Boode
Willem-Pieter
WP
Dilling
Jildau
J
Garcia
Paula
P
Henriques
Margarida
M
Rebelo
Olinda
O
ter Laak
Henk
H
Minetti
Carlo
C
Bruno
Claudio
C
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