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Three novel mutations in Iranian patients with Tay-Sachs disease.

ABSTRACT: BACKGROUND:Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population. METHODS:In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion. RESULTS:Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation. CONCLUSION:In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.

SUBMITTER: Jamali S

PROVIDER: S-EPMC3933921 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Three novel mutations in Iranian patients with Tay-Sachs disease.

Jamali Solmaz S Eskandari Nasim N Aryani Omid O Salehpour Shadab S Zaman Talieh T Kamalidehghan Behnam B Houshmand Massoud M

Iranian biomedical journal 20140101 2

<h4>Background</h4>Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population.<h4>Methods</h4>In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion.<h4>Results</h4>Molecular gene ...[more]

PMID: 24518553

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Project description:Tay-Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of ?-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay-Sachs disease in nine patients confirmed by the deficiency of ?-hexosaminidase-A (< 2% of total hexosaminidase activity for infantile patients) in leucocytes. The enzyme activity was assessed by using substrates 4-methylumbelliferyl-N-acetyl-?-d-glucosamine and 4-methylumbelliferyl-N-acetyl-?-d-glucosamine-6-sulfate for total-hexosaminidase and hexosaminidase-A respectively, and heat inactivation method for carrier detection. The exons and exon-intron boundaries of the HEXA gene were bi-directionally sequenced on an automated sequencer. 'In silico' analyses for novel mutations were carried out using SIFT, Polyphen2 and MutationT@ster software programs. The structural study was carried out by UCSF Chimera software using the crystallographic structure of ?-hexosaminidase-A (PDB-ID: 2GJX) as the template. Our study identified four novel mutations in three cases. These include a compound heterozygous missense mutation c.524A>C (D175A) and c.805G>C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A>C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C>T (p.R178C), (ii) c.964G>T (p.D322Y), and (iii) c.1385A>T (p.E462V); two nonsense mutations (i) c.709C>T (p.Q237X) and (ii) c.1528C>T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G>A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay-Sachs disease with clustering of ~ 73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.

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Three novel mutations in Iranian patients with Tay-Sachs disease.

Publications

Three novel mutations in Iranian patients with Tay-Sachs disease.

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