title: A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain.
abstract: Mucolipidosis (ML) II and ML IIIα/β are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIα/β are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A>C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A>C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIα/β in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A>C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotype-phenotype correlation in ML II and ML IIIα/β and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.
authors.affiliation: Department of Clinical Genetics, Greenwood Genetic Center, Charleston Office, North Charleston, SC, USA.
authors.forename: Jules G
authors.initials: JG
authors.lastname: Leroy
authors.affiliation: The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.affiliation: Department of Clinical Genetics, Greenwood Genetic Center, Charleston Office, North Charleston, SC, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Wood
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
authors.forename: Jarrod
authors.initials: J
authors.lastname: Barnes
authors.affiliation: State University of New York Upstate Medical School, Syracuse, New York, USA.
authors.forename: Robert Roger
authors.initials: RR
authors.lastname: Lebel
authors.affiliation: Department of Clinical Genetics, Greenwood Genetic Center, Charleston Office, North Charleston, SC, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Friez
authors.affiliation: Department of Clinical Genetics, Greenwood Genetic Center, Charleston Office, North Charleston, SC, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Steet
authors.affiliation: Department of Clinical Genetics, Greenwood Genetic Center, Charleston Office, North Charleston, SC, USA.
authors.forename: Sara S
authors.initials: SS
authors.lastname: Cathey
mesh_terms: D000483:Alleles; D002402:Cathepsin D / Q000378:metabolism; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005091:Exons; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009081:Mucolipidoses / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D009154:Mutation; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D035781:Siblings; D017855:Transferases (Other Substituted Phosphate Groups) / Q000737:chemistry / Q000235:genetics*
chemical_list: D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human; D002402:Cathepsin D
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