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Clinical, biochemical and molecular characterization of Korean patients with mucolipidosis II/III and successful prenatal diagnosis.

ABSTRACT: 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.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.We found 14 mutant alleles including seven known mutations of c.2189delT (p.Leu730fs*7), c.1090C?>?T (p.Arg364*), c.2681G?>?A (p.Trp894*), c.3565C?>?T (p.Arg1189*), c.310C?>?T (p.Gln104*), c.1071G?>?A (p.Trp357*) and c.2574_2575delGA (p.Asn859Glnfs*2). Four were novel variants of unknown significance: c.992A?>?G (p.Tyr331Cys), c.2666 T?>?A (p.Leu889*), c.637-6 T?>?G (p.Thr213Phefs*11), and c.471_472delTT (p.Tyr158Serfs*8). Family studies revealed the probands to be compound heterozygotes. The fetuses carried the same GNPTAB mutations as the mucolipidosis II/III probands in the prenatal diagnosis.We identified GNPTAB mutations in all patients with ML II/III, but did not identify a hot spot in Korean patients. We successfully performed prenatal diagnosis using molecular investigation.

SUBMITTER: Yang M

PROVIDER: S-EPMC5240260 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Clinical, biochemical and molecular characterization of Korean patients with mucolipidosis II/III and successful prenatal diagnosis.

Yang Mina M Cho Sung Yun SY Park Hyung-Doo HD Choi Rihwa R Kim Young-Eun YE Kim Jinsup J Lee Soo-Youn SY Ki Chang-Seok CS Kim Jong-Won JW Sohn Young Bae YB Song Junghan J Jin Dong-Kyu DK

Orphanet journal of rare diseases 20170117 1

<h4>Background</h4>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.<h4>Method ...[more]

PMID: 28095893

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Project description:Mucolipidosis II α/β, mucolipidosis III α/β, and mucolipidosis III γ are autosomal recessive disorders belonging to the family of lysosomal storage disorders caused by deficiency of the UDP-N-acetylglucosamine, a lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) localized in the Golgi apparatus, which is essential for normal processing and packaging of soluble lysosomal enzymes with initiating the first step of tagging lysosomal enzymes with mannose-6-phosphate (M6P). Mucolipidosis II and III are caused by mutations in the GNPTAB and GNPTG genes, and patients with these diseases are characterized by short stature, skeletal abnormalities, and developmental delay. In this study we report 38 patients with mucolipidosis II and III enrolled in Eastern China during the past 8 years. The diagnosis was made based on clinical characteristics and measurement of plasma lysosomal enzyme activity. Sanger sequencing of GNPTAB and/or GNPTG for all patients and real-time quantitative PCR were performed to confirm the diagnosis. In addition, 11 cases of prenatal mucolipidosis II were diagnosed based on measurement of the enzyme activity in amniotic fluid supernatant and genetic testing of cultured amniotic cells. Based on molecular genetic tests, 30 patients were diagnosed with mucolipidosis II α/β, 6 were diagnosed with III α/β and 2 were diagnosed with III γ. Thirty-seven different GNPTAB gene mutations were identified in 29 patients with mucolipidosis II α/β and six patients with III α/β. These mutations included 22 new mutations (p.W44X, p.E279X, p.W416X, p.W463X, p.Q802X, p.Q882X, p.A34P, p.R334P, p.D408N, p.D534N, p.Y997C, p.D1018V, p.L1025S, p.L1033P, c.88_89delAC, c.890_891insT, c.1150_1151insTTA, c.1523delG, c.2473_2474insA, c.2980_2983delGCCT, c.3094delA, and deletion of exon 9). Four new GNPTG gene mutations were identified (c.13delC, p.Y81X, p.G126R and c.609+1delG) in two mucolipidosis III γ patients. Among the 11 cases of prenatal diagnosis, four were mucolipidosis II fetuses, three were heterozygous, and the remaining four were normal fetuses. This study expands the mutation spectrum of the GNPTAB and GNPTG genes and contributes to specific knowledge of mucolipidosis II/III in a population from Eastern China.

Dataset Information

Clinical, biochemical and molecular characterization of Korean patients with mucolipidosis II/III and successful prenatal diagnosis.

Publications

Clinical, biochemical and molecular characterization of Korean patients with mucolipidosis II/III and successful prenatal diagnosis.

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