For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
3
views
7
references
 Top references
cited by
1
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      451
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Identification of deletion-duplication in HEXA gene in five children with Tay-Sachs disease from India

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion.

          Methods

          Multiplex Ligation-dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not be identified in the coding region by sequencing of HEXA gene.

          Results

          The study has identified the presence of a homozygous deletion of exon-2 and exon-3 in two patients, two patient showed compound heterozygosity with exon 1 deletion combined with missense mutation p.E462V and one patient was identified with duplication of exon-1 with novel variants c.1527-2A > T as a second allele.

          Conclusion

          This is the first report of deletion/duplication in HEXA gene providing a new insight into the molecular basis of TSD and use of MLPA assay for detecting large copy number changes in the HEXA gene.

          Related collections

          Most cited references7

          • Record: found
          • Abstract: found
          • Article: not found

          Biochemical consequences of mutations causing the GM2 gangliosidoses.

          Don J. Mahuran (1999)
          The hydrolysis of GM2-ganglioside is unusual in its requirements for the correct synthesis, processing, and ultimate combination of three gene products. Whereas two of these proteins are the alpha- (HEXA gene) and beta- (HEXB) subunits of beta-hexosaminidase A, the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate specific co-factor for the enzyme. A deficiency of any one of these proteins leads to storage of the ganglioside, primarily in the lysosomes of neuronal cells, and one of the three forms of GM2-gangliosidosis, Tay-Sachs disease, Sandhoff disease or the AB-variant form. Studies of the biochemical impact of naturally occurring mutations associated with the GM2 gangliosidoses on mRNA splicing and stability, and on the intracellular transport and stability of the affected protein have provided some general insights into these complex cellular mechanisms. However, such studies have revealed little in the way of structure-function information on the proteins. It appears that the detrimental effect of most mutations is not specifically on functional elements of the protein, but rather on the proteins' overall folding and/or intracellular transport. The few exceptions to this generalization are missense mutations at two codons in HEXA, causing the unique biochemical phenotype known as the B1-variant, and one codon in both the HEXB and GM2A genes. Biochemical characterization of these mutations has led to the localization of functional residues and/or domains within each of the encoded proteins.
          Article 0 comments Cited 49 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures.

            V Chigorno, S Sonnino (2000)
            Gangliosides exist as a very complex mixture of species differing in both the hydrophilic and hydrophobic moieties. They are particularly abundant in the central nervous system (CNS), where they have been associated with development and maturation of the brain, neuritogenesis, synaptic transmission, memory formation and synaptic aging. Today, many data suggest that some of the effects exerted by gangliosides are due to interactions with proteins that participate in the transduction of signals through the membrane in membrane microdomains. A specific characteristic of CNS gangliosides is the structure of their long-chain base (LCB). In fact, considering all the mammalian cell sphingolipids, gangliosides, sulphatides, neutral glycosphingolipids, sphingomyelin and ceramides, it would seem that while the LCB with 18 carbons is the main component of all sphingolipids, only CNS gangliosides contain significant amounts of LCB with 20 carbons. C18-Sphingosine is always present in cell gangliosides; the individual ganglioside species containing C18-sphingosine increase during cell differentiation then remain constant during cell aging. Gangliosides containing C20-sphingosine are absent, or present only in traces, in undifferentiated cells but with the onset of cell differentiation they appear, their content slowly but continuously increasing throughout the life span. In this review we discuss the chemistry, physico-chemistry and metabolism of ganglioside species differing in LCB length and introduce the hypothesis that the varying ratio between C18- and C20-gangliosides during CNS development and aging can be instrumental in modulating membrane domain organisation and cell properties.
            Article 0 comments Cited 23 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Identification of Novel Mutations in HEXA Gene in Children Affected with Tay Sachs Disease from India

              Mehul Mistri, Parag M Tamhankar, Frenny Sheth … (2012)
              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.
              Article 0 comments Cited 19 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Jayesh Sheth:
                ORCID: http://orcid.org/0000-0001-5936-5192
                91-79-26921414 , jshethad1@gmail.com
                Mehul Mistri: mistrimehul@yahoo.co.in
                Lakshmi Mahadevan: lakshmi.m@medgenome.com
                Sanjeev Mehta: drsjmehta007@gmail.com
                Dhaval Solanki: drdhavalsolanki@gmail.com
                Mahesh Kamate: drmaheshkamate@gmail.com
                Frenny Sheth: fshethad1@googlemail.com
                Journal
                Journal ID (nlm-ta): BMC Med Genet
                Journal ID (iso-abbrev): BMC Med. Genet
                Title: BMC Medical Genetics
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2350
                Publication date (Electronic): 4 July 2018
                Publication date PMC-release: 4 July 2018
                Publication date Collection: 2018
                Volume: 19
                Electronic Location Identifier: 109
                Affiliations
                [1 ]ISNI 0000 0001 2154 7601, GRID grid.411494.d, Biochemical and Molecular Genetics, FRIGE’s Institute of Human Genetics, ; FRIGE House, Satellite, Ahmedabad, Gujarat 380 015 India
                [2 ]Medgenome Labs Pvt Ltd, Bangalore, India
                [3 ]Usha Deep Hospital, Ahmedabad, Gujarat India
                [4 ]Mantra Child Neurology & Epilepsy Clinic, Bhavnagar, Gujarat India
                [5 ]Department of Pediatric Neurology, KLES Prabhakar Kore Hospital, Belgaum, Karnataka India
                Author information
                http://orcid.org/0000-0001-5936-5192
                Article
                Publisher ID: 632
                DOI: 10.1186/s12881-018-0632-7
                PMC ID: 6032535
                PubMed ID: 29973161
                SO-VID: 2beed4e4-51f0-40e7-82ba-c77a736c44be
                Copyright © © The Author(s). 2018
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 26 October 2017
                Date accepted : 25 June 2018
                Funding
                Funded by: Indian Council of Medical Research and Department of Heath Research,Govt of India
                Award ID: BMS-54/2009
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2018

                ScienceOpen disciplines: Genetics
                Keywords: tay-sachs disease,ß-hexosaminidase-a,hexa gene; mlpa
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: tay-sachs disease, ß-hexosaminidase-a, hexa gene; mlpa

                Comments

                Comment on this article

                scite_

                Similar content451

                See all similar

                Cited by1

                See all cited by

                Most referenced authors155

                See all reference authors