Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.

Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The...

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Autores principales:	Mehul Mistri, Parag M Tamhankar, Frenny Sheth, Daksha Sanghavi, Pratima Kondurkar, Swapnil Patil, Susan Idicula-Thomas, Sarita Gupta, Jayesh Sheth
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ab9224512e654c88a04c5b2bc0563030
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spelling	oai:doaj.org-article:ab9224512e654c88a04c5b2bc05630302021-11-18T07:15:09ZIdentification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.1932-620310.1371/journal.pone.0039122https://doaj.org/article/ab9224512e654c88a04c5b2bc05630302012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22723944/?tool=EBIhttps://doaj.org/toc/1932-6203Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.Mehul MistriParag M TamhankarFrenny ShethDaksha SanghaviPratima KondurkarSwapnil PatilSusan Idicula-ThomasSarita GuptaJayesh ShethPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 6, p e39122 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mehul Mistri Parag M Tamhankar Frenny Sheth Daksha Sanghavi Pratima Kondurkar Swapnil Patil Susan Idicula-Thomas Sarita Gupta Jayesh Sheth Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.
description	Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.
format	article
author	Mehul Mistri Parag M Tamhankar Frenny Sheth Daksha Sanghavi Pratima Kondurkar Swapnil Patil Susan Idicula-Thomas Sarita Gupta Jayesh Sheth
author_facet	Mehul Mistri Parag M Tamhankar Frenny Sheth Daksha Sanghavi Pratima Kondurkar Swapnil Patil Susan Idicula-Thomas Sarita Gupta Jayesh Sheth
author_sort	Mehul Mistri
title	Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.
title_short	Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.
title_full	Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.
title_fullStr	Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.
title_full_unstemmed	Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.
title_sort	identification of novel mutations in hexa gene in children affected with tay sachs disease from india.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/ab9224512e654c88a04c5b2bc0563030
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Identification of novel mutations in HEXA gene in children affected with Tay Sachs disease from India.

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