Abstract
Introduction Mucolipidosis type II alpha/beta (MLII or I-cell disease) (MIM 252500) is a rare inborn lysosomal hydrolase trafficking disorder caused by the deficient activity of N-acetylglucosaminyl 1-phospho (NAcGlc-1-P) transferase, the enzyme responsible for the initial step in the generation of the mannose 6-phosphate recognition marker. NAcGlc-1-P-transferase is a multimeric enzyme composed of 3 polypeptide subunits (α, β and γ) encoded by 2 different genes. The gene encoding for the α/β subunits ( GNPTAB), located on chromosome 12q23.3, is altered in MLII. To date, at least 20 missense/nonsense GNPTAB mutations have been described and incriminated in this autosomal recessive disorder. In this study, we characterized the molecular defect of a new case of MLII, presenting important skeletal abnormalities. Material and methods The activity of lysosomal hydrolases in the patient's fibroblasts, plasma and cell culture medium was determined using appropriate fluorogenic substrates. All exons, as well as exon-intron boundaries, of the GNPTAB gene were sequenced after PCR amplification of the patient's genomic DNA. GNPTAB exon 11 was also studied by enzyme restriction analysis in the whole family. Results In the patient's fibroblasts, a residual activity of lysosomal hydrolases averaging 14% of control values was found, while a 32 and 9-fold increase in the activity of these enzymes was detected in plasma and the fibroblast culture medium, respectively. Two novel nonsense disease-associated GNPTAB mutations, c.1383C > A (p.Cys461X) and c.3410T > A (p.Leu1136X) were identified, the patient being a compound heterozygote. Conclusions Characterization of the GNPTAB molecular defects in a new case of MLII and the identification of two novel nonsense mutations facilitated the prenatal diagnosis of this disease in the patient's family.
Published Version
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