Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease
Tay–Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-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...
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doaj-5c5fcf7d32e349658997f18d94d59aef2020-11-24T23:08:31ZengElsevierMolecular Genetics and Metabolism Reports2214-42692014-01-011C42543010.1016/j.ymgmr.2014.09.004Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs diseaseJayesh Sheth0Mehul Mistri1Chaitanya Datar2Umesh Kalane3Shekhar Patil4Mahesh Kamate5Harshuti Shah6Sheela Nampoothiri7Sarita Gupta8Frenny Sheth9Department of Biochemical and Molecular Genetics, FRIGE's Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad 380015, IndiaDepartment of Biochemical and Molecular Genetics, FRIGE's Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad 380015, IndiaDepartment of Genetics, Clinical Geneticist, Sahyadri Medical Genetics and Tissue Engineering Facility (SMGTEF), Pune, IndiaDepartment of Genetics, Clinical Geneticist, Sahyadri Medical Genetics and Tissue Engineering Facility (SMGTEF), Pune, IndiaDepartment of Pediatric Neurology, Hiranandani Hospital, Mumbai, Maharashtra, IndiaDepartment of Pediatric Neurology, KLES Prabhakar Kore Hospital, Belgaum, Karnataka, IndiaRajvee Child Neuro Hospital, Memnagar, Ahmedabad, IndiaDepartment of Pediatric Genetics, Amrita Institute of Medical Science & Research Centre, AIMS Ponekkara PO, Cochin, Kerala, IndiaDepartment of Biochemistry, Faculty of Science, M.S. University of Baroda, Vadodara, Gujarat, IndiaDepartment of Biochemical and Molecular Genetics, FRIGE's Institute of Human Genetics, FRIGE House, Satellite, Ahmedabad 380015, IndiaTay–Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-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 β-hexosaminidase-A (<2% of total hexosaminidase activity for infantile patients) in leucocytes. The enzyme activity was assessed by using substrates 4-methylumbelliferyl-N-acetyl-β-d-glucosamine and 4-methylumbelliferyl-N-acetyl-β-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 β-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.http://www.sciencedirect.com/science/article/pii/S2214426914000627Tay–Sachs diseaseHEXA geneβ-Hexosaminidase-ALysosomal enzyme |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jayesh Sheth Mehul Mistri Chaitanya Datar Umesh Kalane Shekhar Patil Mahesh Kamate Harshuti Shah Sheela Nampoothiri Sarita Gupta Frenny Sheth |
spellingShingle |
Jayesh Sheth Mehul Mistri Chaitanya Datar Umesh Kalane Shekhar Patil Mahesh Kamate Harshuti Shah Sheela Nampoothiri Sarita Gupta Frenny Sheth Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease Molecular Genetics and Metabolism Reports Tay–Sachs disease HEXA gene β-Hexosaminidase-A Lysosomal enzyme |
author_facet |
Jayesh Sheth Mehul Mistri Chaitanya Datar Umesh Kalane Shekhar Patil Mahesh Kamate Harshuti Shah Sheela Nampoothiri Sarita Gupta Frenny Sheth |
author_sort |
Jayesh Sheth |
title |
Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease |
title_short |
Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease |
title_full |
Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease |
title_fullStr |
Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease |
title_full_unstemmed |
Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease |
title_sort |
expanding the spectrum of hexa mutations in indian patients with tay–sachs disease |
publisher |
Elsevier |
series |
Molecular Genetics and Metabolism Reports |
issn |
2214-4269 |
publishDate |
2014-01-01 |
description |
Tay–Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-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 β-hexosaminidase-A (<2% of total hexosaminidase activity for infantile patients) in leucocytes. The enzyme activity was assessed by using substrates 4-methylumbelliferyl-N-acetyl-β-d-glucosamine and 4-methylumbelliferyl-N-acetyl-β-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 β-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. |
topic |
Tay–Sachs disease HEXA gene β-Hexosaminidase-A Lysosomal enzyme |
url |
http://www.sciencedirect.com/science/article/pii/S2214426914000627 |
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