A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

Abstract

Mucolipidosis (ML) II and ML IIIa/b 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 IIIa/b 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.10A4C 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.10A4C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIa/b 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.10A4C/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 genotypephenotype correlation in ML II and ML IIIa/b and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.

Mislocalization of phosphotransferase as a cause of mucolipidosis III αβ

“…Interestingly, a recent study reported that MLIII αβ patients with the K4Q mutation share a specific phenotype, one that is intermediate between MLII and MLIII αβ (8). Both of these lysosomal storage disorders are caused by mutations in GNPTAB, but MLII patients have a greater loss of phosphotransferase activity, which results in a more severe phenotype.…”

“…In this study, the effect of two missense mutations in the N-terminal cytoplasmic tail of the α subunit of phosphotransferase, Lys4Gln (K4Q) and Ser15Tyr (S15Y) (6)(7)(8), was investigated (Fig. 1A).…”

Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs

“…However, the Tomatsu et al study only included 11 samples, and the type of ML, or clinical severity, was not indicated. We analyzed urine KS in 51 samples from ML patients with a well-defined clinical phenotype and a confirmed diagnosis of either ML II, ML II/III, or ML III (Leroy et al 2014;Lyseng-Williamson 2014). Urine KS was elevated in all samples from patients with ML II or ML II/III and the average urine KS level in these patients (fourfold increase relative to age-matched controls) was approximately the same as that in MPS IVA patients (4.7-fold increase).…”

Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders

“…29 Patients with mucolipidosis II usually have a short lifespan, commonly resulting in death in early childhood because of cardiorespiratory problems. [35][36][37] Cardiorespiratory abnormalities are similar to those seen in MPS I (Hurler syndrome), including cardiac valve problems, thickening of the airways and thoracic cage stiffening. 35 Other clinical similarities between mucolipidosis II and MPS I may include dysostosis multiplex (Figure 10), short stature and coarse facies.…”

“…This causes a deficiency in N-acetylglucosamine-1 phosphotransferase, which results in lysosomal acid hydrolase enzymes lacking a normal recognition phosphate group and abnormally accumulating in the extracellular space rather than the lysosome. 35 Mucolipidosis II has autosomal recessive inheritance, with a worldwide prevalence of 0.15/100 000live births. 29 Patients with mucolipidosis II usually have a short lifespan, commonly resulting in death in early childhood because of cardiorespiratory problems.…”