Recurrent and novel GLB1 mutations in India

Bidchol, Abdul Mueed; Dalal, Ashwin; Trivedi, Rakesh; Shukla, Anju; Nampoothiri, Sheela; Sankar, V.H.; Danda, Sumita; Gupta, Neerja; Kabra, Madhulika; Hebbar, Shripad; Bhat, Ramesh Y; Matta, Divya; Ekbote, Alka V.; Puri, Ratna Dua; Phadke, Shubha R.; Gowrishankar, Kalpana; Aggarwal, Shagun; Ranganath, Prajnya; Sharda, Sheetal; Kamate, Mahesh; Datar, Chaitanya; Bhat, Kamalakshi G.; Kamath, Nutan; Shah, Hitesh; Krishna, Shuba; Gopinath, P. M.; Verma, Ishwar C.; Nagarajaram, Hampapathalu A.; Satyamoorthy, Kapaettu; Girisha, Katta M.

doi:10.1016/j.gene.2015.04.078

Cited by 21 publications

(19 citation statements)

References 43 publications

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“…The gene GLB1 is mapped on chromosome 3 in the locus 3p21.33, is 62.5 kb long, consists of 16 exons and encodes 677 aminoacid residues of acid β-galactosidase, including 23 aminoacids of the signaling peptide [6]. The molecule of human acid β-galactosidase is a protein, consisting of three domains (the main catalytic TIM barell domain and β1-and β2-domain), which exist in the monomer form at neutral pH [2].…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of six new mutations in GLB1 gene in Ukrainian patients with GM1 gangliosidosis and Morquio B disease

Mytsyk

Горовенко

2016

Biopolym. Cell

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Section: Introductionmentioning

confidence: 99%

“…In conditions of acid pH of the lysosome (pH 4-5) the molecule of human β-galactosidase acquires its active form by dimerization. At present 144 mutations in the gene GLB1 have been described, 109 of which are missence/ nonsense mutations, 14 -deletions, 10 -insertions, 11 -mutations, causing splicing disorders [6].…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of six new mutations in GLB1 gene in Ukrainian patients with GM1 gangliosidosis and Morquio B disease

Mytsyk

Горовенко

2016

Biopolym. Cell

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“…In the current Glb1 −/− mice, an insertion into exon 15 resulted in exon skipping and consequently generation of a shortened dysfunctional protein. Exon 15 is located in the beta domain 2 of β-galactosidase [25], which is necessary for proteolytic processing and enzyme activity, but not for the transport to lysosomes in dogs and humans [119]. In humans, various mutations of the β-galactosidase have been described [25][26][27][28][120][121][122], many of which affect mRNA splicing [123], frequently resulting in exon skipping [11] and a non-functional enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Exon 15 is located in the beta domain 2 of β-galactosidase [25], which is necessary for proteolytic processing and enzyme activity, but not for the transport to lysosomes in dogs and humans [119]. In humans, various mutations of the β-galactosidase have been described [25][26][27][28][120][121][122], many of which affect mRNA splicing [123], frequently resulting in exon skipping [11] and a non-functional enzyme. Very low enzymatic activities of the murine β-galactosidase were present in the current mouse model resembling human [25,26,124], canine [9,11,65] and murine [22,23] G M1 -gangliosidosis.…”

Section: Discussionmentioning

confidence: 99%

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

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GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

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“…4 There have been several case reports describing the usual presentation of this disease. [5][6][7][8][9][10][11] This study is the single largest unicentric study of GM1 gangliosidosis in the pediatric population from the Indian subcontinent. All our cases of GM1 gangliosidosis had neurodevelopmental problems.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Laboratory Profile of Gangliosidosis from Southern Part of India

et al. 2020

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Gangliosidoses are progressive neurodegenerative disorders caused by the deficiency of enzymes involved in the breakdown of glycosphingolipids. There are not much data about gangliosidosis in India; hence, this study was planned. The aim is to study the clinical, biochemical, and molecular profile of gangliosidosis. A retrospective chart review, in the pediatric neurology department from January 2015 to March 2020, was performed. Children diagnosed with Gangliosidosis were included. The disorder was confirmed by reduced activity of enzymes and/or pathogenic or likely pathogenic variants in associated genes. We assessed age at presentation, gender, parental consanguinity, clinical manifestations, neuroimaging findings, enzyme level, and pathogenic or likely pathogenic variants. Clinical data for 32 children with gangliosidosis were analyzed, which included 12 (37.5%) with GM1 gangliosidosis, 8 (25%) with Tay-Sachs disease (TSD), 11 (34.37%) with Sandhoff disease (SD), and 1 AB variant of GM2 gangliosidosis that occurs due to GM2 ganglioside activator protein deficiency. Twenty-four (75%) children were the offspring of consanguineous parents. Thirty-one (97%) had developmental delay. The median age at presentation was 15.5 months. Nine (28.12%) had seizures. Five children (41.6%) with GM1 gangliosidosis and two with SD had extensive Mongolian spots. Ten children with GM1 gangliosidosis (83.3%) had coarse facial features. Cherry red spot was found in 24 out of 32 children (75%). All children with GM1 gangliosidosis and none with TSD had hepato-splenomegaly. Two children (2/8; 25%) with TSD and seven (7/11; 63%) with SD had microcephaly. One child with SD had coarse facies and three did not have hepato-splenomegaly. Neuroimaging findings revealed bilateral thalamic involvement in 20 (62.5%) patients and periventricular hypomyelination in all cases. One child had a rare AB variant of GM2 gangliosidosis. GM2 Gangliosidoses are more common compared with GM1 variety. All of them had infantile onset except one child with TSD. Microcephaly can be present while usually megalencephaly is reported in the literature. The absence of hepato-splenomegaly does not rule out SD. Extensive Mongolian spots can be seen in GM2 gangliosidosis. AB variant of GM2 gangliosidosis should be considered when the enzyme is normal in the presence of strong clinical suspicion.

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Recurrent and novel GLB1 mutations in India

Cited by 21 publications

References 43 publications

Identification and characterization of six new mutations in GLB1 gene in Ukrainian patients with GM1 gangliosidosis and Morquio B disease

Identification and characterization of six new mutations in GLB1 gene in Ukrainian patients with GM1 gangliosidosis and Morquio B disease

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Clinical and Laboratory Profile of Gangliosidosis from Southern Part of India

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