Abstract:Mucolipidosis (ML) II (I-cell disease) is a lysosomal storage disorder caused by a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII-deceased children from the SLSJ region as obligatory and potential c… Show more
“…The mutation encountered most often, both in the literature data and in this study (c.3503delTC), has been reported as the single causal mutation in the GNPTAB gene in a French-Canadian founder population. 33 In a recent report, Otomo et al 36 analysed GNPTAB in 40 Japanese patients. The most common mutation in that population (c.3565C>T, R1189X) was detected in four of our probands: two US Caucasians, one Hispanic and one New Zealander.…”
Objectives
Mucolipidoses II and III alpha/beta (ML II and ML III) are lysosomal disorders in which the essential mannose-6-phosphate recognition marker is not synthesized onto lysosomal hydrolases and other glycoproteins. The disorders are caused by mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. Clinical, biochemical, and molecular findings in 61 probands (63 patients) are presented in order to provide a broad perspective of these mucolipidoses.
Methods
GNPTAB was sequenced in all probands and/or parents. Activity of several lysosomal enzymes was measured in plasma, and GlcNac-1-phosphotransferase was assayed in leukocytes. Thirty-six patients were studied in detail, allowing extensive clinical data to be abstracted.
Results
ML II correlates with near total absence of phosphotransferase activity resulting from homozygosity or compound heterozygosity for frameshift or nonsense mutations. Craniofacial and orthopedic manifestations are evident at birth, skeletal findings become more obvious within the first year, and growth is severely impaired. Speech, ambulation, and cognitive function are impaired. ML III retains a low level of phosphotransferase activity due to at least one missense or splice site mutation. The phenotype is milder with minimal delays in milestones, the appearance of facial coarsening by early school age, and slowing of growth after age four years.
Conclusions
Fifty-one pathogenic changes in GNPTAB are presented, including 42 novel mutations. Ample clinical information improves criteria for delineation of ML II and ML III. Phenotype-genotype correlations suggested in more general terms in earlier reports on smaller groups of patients are specified and extended.
“…The mutation encountered most often, both in the literature data and in this study (c.3503delTC), has been reported as the single causal mutation in the GNPTAB gene in a French-Canadian founder population. 33 In a recent report, Otomo et al 36 analysed GNPTAB in 40 Japanese patients. The most common mutation in that population (c.3565C>T, R1189X) was detected in four of our probands: two US Caucasians, one Hispanic and one New Zealander.…”
Objectives
Mucolipidoses II and III alpha/beta (ML II and ML III) are lysosomal disorders in which the essential mannose-6-phosphate recognition marker is not synthesized onto lysosomal hydrolases and other glycoproteins. The disorders are caused by mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. Clinical, biochemical, and molecular findings in 61 probands (63 patients) are presented in order to provide a broad perspective of these mucolipidoses.
Methods
GNPTAB was sequenced in all probands and/or parents. Activity of several lysosomal enzymes was measured in plasma, and GlcNac-1-phosphotransferase was assayed in leukocytes. Thirty-six patients were studied in detail, allowing extensive clinical data to be abstracted.
Results
ML II correlates with near total absence of phosphotransferase activity resulting from homozygosity or compound heterozygosity for frameshift or nonsense mutations. Craniofacial and orthopedic manifestations are evident at birth, skeletal findings become more obvious within the first year, and growth is severely impaired. Speech, ambulation, and cognitive function are impaired. ML III retains a low level of phosphotransferase activity due to at least one missense or splice site mutation. The phenotype is milder with minimal delays in milestones, the appearance of facial coarsening by early school age, and slowing of growth after age four years.
Conclusions
Fifty-one pathogenic changes in GNPTAB are presented, including 42 novel mutations. Ample clinical information improves criteria for delineation of ML II and ML III. Phenotype-genotype correlations suggested in more general terms in earlier reports on smaller groups of patients are specified and extended.
“…This is useful for predicting prognosis to analyze mutations for treatment, including hematopoietic stem cell transplantation, especially in attenuated cases diagnosed in the early stage by molecular analysis. 16 According to the recent report, 17 23 different mutations have been reported in the GNPTAB gene causing ML II and III alpha/beta. We detected 14 new mutations in the Japanese population.…”
“…In a Korean population, the most frequently observed mutation was c.3565C > T (p.Arg1189*) (11.5%, 5/26 alleles), excluding the overlapping case of siblings, but the difference in frequency compared to the second most common mutation (c.2574_2575delGA, 7.7%) was not large. The c.3503delTC mutation, known as a single causal mutation in a French-Canadian founder population [21], was the most frequently encountered mutation in the largest study in a Western population [19]. Considering that c.3503delTC has not been observed in Asian populations, the spectrum of mutation type seems to exhibit ethnic differences.Fig.…”
Background: Mucolipidosis types II and III (ML II/III) are autosomal recessive disorders caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. We investigated the molecular genetic characteristics of the GNPTAB gene, which codes for the alpha/beta subunits of a phosphotransferase, in Korean ML II/III patients. We included prenatal tests and evaluated the spectrum of mutations in East Asian populations with ML II/III through a literature review. Methods: Seven patients from six families were enrolled in the study including two prenatal tests using chorionic villi samples. A diagnosis of ML II/III was made based on clinical findings and increases in serum lysosomal enzyme levels. PCR and direct sequencing were performed to identify GNPTAB mutations.
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