title: Hepatic and neuromuscular forms of glycogenosis type III: nine mutations in AGL.
abstract: Glycogenosis type III (Cori disease) is an autosomal recessive disorder caused by the deficiency of the glycogen debranching enzyme, encoded by the AGL gene, and existing in six isoforms alternately spliced in a tissue-specific way. Generally, disease onset occurs early on starting from the first year of life, with hepatomegaly, hypoglycemia, hyperlipidemia, increased CK levels, and, in some cases, short stature and slight mental retardation. Frequently, hepatomegaly tends to resolve spontaneously and inexplicably during childhood, when myopathy, often associated with cardiomyopathy, arises. This disease is known to lack almost invariably clear links between the genotype and clinical phenotype. We describe nine new mutations in Italian patients: four nonsense (p.Arg285X, p.Lys422X, p.Arg910X, p.Arg977X), three frameshift (c.442delA, c.753_756delGACA, c.3963delG), and two missense (p.Ala1120Pro, p.Arg524His). Particularly, the nonsense p.Arg285X is linked to an exonic splicing enhancer and it was found to produce two species of transcripts at the same time. Moreover, we discuss a subgroup of subjects carrying c.2681+1G>A, which has proven to be the most frequent mutation among our patients. The previously described c.664+3A>G was also detected in two patients, both homozygous. The present work is yet another confirmation that the individual genetic background plays a pivotal role in influencing the phenotypes, as occurs in other metabolic diseases.
authors.affiliation: Dino Ferrari Center, Department of Neurological Sciences, University of Milan, Fondazione I.R.C.C.S. Ospedale Maggiore Policlinico, Mangialli, Regina Elena, Milan, Italy. sabrina.lucchiari@unimi.it
authors.forename: S
authors.initials: S
authors.lastname: Lucchiari
authors.forename: S
authors.initials: S
authors.lastname: Pagliarani
authors.forename: S
authors.initials: S
authors.lastname: Salani
authors.forename: M
authors.initials: M
authors.lastname: Filocamo
authors.forename: M
authors.initials: M
authors.lastname: Di Rocco
authors.forename: D
authors.initials: D
authors.lastname: Melis
authors.forename: C
authors.initials: C
authors.lastname: Rodolico
authors.forename: O
authors.initials: O
authors.lastname: Musumeci
authors.forename: A
authors.initials: A
authors.lastname: Toscano
authors.forename: N
authors.initials: N
authors.lastname: Bresolin
authors.forename: G P
authors.initials: GP
authors.lastname: Comi
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D006004:Glycogen Debranching Enzyme System / Q000737:chemistry / Q000235:genetics*; D006010:Glycogen Storage Disease Type III / Q000145:classification / Q000175:diagnosis* / Q000235:genetics; D006529:Hepatomegaly / Q000235:genetics; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009135:Muscular Diseases / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D016415:Sequence Alignment
chemical_list: D018389:Codon, Nonsense; D006004:Glycogen Debranching Enzyme System