Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase α/β subunits in Korean patients with mucolipidosis type II or type IIIA

Abstract

Mucolipidosis types II and III are autosomal recessive inherited diseases caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1 phosphotransferase (GlcNAc-phosphotransferase), which adds phosphate to function as a recognition marker for the uptake and transport of lysosomal enzymes. We investigated mutations in the GNPTA (MGC4170) gene, which codes for the alpha/beta subunits of phosphotransferase, and in the GNPTAG gene, which codes for its gamma subunits in five Korean patients with mucolipidosis type II or IIIA. We identified seven mutations in the GNPTA gene, but none in GNPTAG. The mutations in type II patients included p.Q104X (c.310C>T), p.R1189X (c.3565C>T), p.S1058X (c.3173C>G), p.W894X (c.2681G>A), and p.H1158fsX15 (c.3474_3475delTA), all of which are nonsense or frameshift mutations. However, a splicing site mutation, IVS13+1G>A (c.2715+1G>A) was detected along with a nonsense or a frameshift mutation (p.R1189X or p.E858fsX3 (c.2574_2575delGA)) in two mucolipidosis type IIIA patients. This report shows that mutations in the GNPTA gene coding for the alpha/beta subunits of phosphotransferase, and not mutations in the GNPTAG gene, account for most of the genetic mutations found in Korean patients with mucolipidosis type II or IIIA.

Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype–phenotype correlation

“…Eight of 25 ML II patients have this mutation homozygously. According to previous reports, this mutation was only found in two Korean cases 11 and in one case of Irish/Scottish origin. 13 This mutation seems to be common in eastern Asia, including Japan.…”

“…These include 14 new mutations and four previously detected mutations. All four known mutations were reported by a Korean group 11 and one, p.R1189X, was also reported by an Israeli group in a patient of Irish/Scottish origin. 13 The most frequent mutation was the nonsense mutation p.R1189X (c.3565C4T) and its allele frequency was 33/80 (¼41.25%) in the analyzed alleles of all ML II and III patients.…”

“…This mutation is discussed in detail in the previous article. 11 We examined the founder effects of several mutations based on the result of polymorphisms. We show the genotype frequencies of several polymorphisms in patients with/without p.F374L and c.2715+1G4A (Table 5).…”

“…[7][8][9] Mutations in GNPTAB cause both the severe type of ML (ML II alpha/beta, ML II, I-cell disease (MIM 252500)) and the attenuated type of ML (ML III alpha/beta, ML IIIA, PseudoHurler polydystrophy (MIM 252600)). [10][11][12] Mutations in GNPTG cause the attenuated type of ML (ML III gamma, ML IIIC, ML III variant (MIM 252605)).…”

Missense mutation in theN-acetylglucosamine-1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG

“…Recently, we identified a novel gene, GNPTA, encoding a protein of 1,256 amino acids with two putative transmembrane domains and a complex module structure which is required for proper phosphotransferase activity [Tiede et al, 2005a]. Defects in GNPTA result in mucolipidosis type II (ML II, I-cell disease; MIM# 252500) [Paik et al, 2005;Tiede et al, 2005a;Kudo et al, 2006] whereas mutations in GNPTG were found in ML III patients (pseudo Hurler-polydystrophy; MIM# 252600) [Raas-Rothschild et al, 2000Tiede et al, 2004]. ML II patients are characterized by dwarfism, skeletal abnormalities, developmental delay and cardiomegaly leading to death between 5 and 8 years of age [Kornfeld and Sly, 2001;Spranger et al, 2002].…”