Recurrent and novel GLB1 mutations in India.
GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme β-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, β-domain 1 and β-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India.
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
Abdul Mueed
AM
Bidchol
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
Ashwin
A
Dalal
Laboratory of Computational Biology & Bioinformatics Facility, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India; Graduate Studies, Manipal University, Manipal, Karnataka, India.
Rakesh
R
Trivedi
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
Anju
A
Shukla
Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, Kochi, AIMS Ponekkara, Kerala, India.
Sheela
S
Nampoothiri
Genetic Clinic, Department of Pediatrics, SAT Hospital, Government Medical College, Thiruvananthapuram, Kerala, India.
V H
VH
Sankar
Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.
Sumita
S
Danda
Genetics Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Neerja
N
Gupta
Genetics Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
Madhulika
M
Kabra
Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
Shrikiran A
SA
Hebbar
Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
Ramesh Y
RY
Bhat
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
Divya
D
Matta
Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.
Alka V
AV
Ekbote
Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India.
Ratna Dua
RD
Puri
Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
Shubha R
SR
Phadke
Department of Medical Genetics, Childs Trust Medical Research Foundation, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India.
Kalpana
K
Gowrishankar
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India; Department of Medical Genetics, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.
Shagun
S
Aggarwal
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India; Department of Medical Genetics, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.
Prajnya
P
Ranganath
Post Graduate Institute of Medical Education and Research, Chandigarh, Punjab, India.
Sheetal
S
Sharda
Pediatric Neurology, KLE University's J N Medical College, Belgaum, Karnataka, India.
Mahesh
M
Kamate
Rare Genetic Disorder Clinic, Sahyadri Hospital, Pune, Maharashtra, India.
Chaitanya A
CA
Datar
Department of Pediatrics, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.
Kamalakshi
K
Bhat
Department of Pediatrics, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.
Nutan
N
Kamath
Pediatric Orthopedics Services, Department of Orthopedics, Kasturba Medical College, Manipal, Manipal University, Karnataka, India.
Hitesh
H
Shah
Strand Life Sciences Pvt Ltd, Bengaluru, Karnataka, India.
Shuba
S
Krishna
Division of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
Puthiya Mundyat
PM
Gopinath
Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India.
Ishwar C
IC
Verma
Laboratory of Computational Biology & Bioinformatics Facility, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
H A
HA
Nagarajaram
Division of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
Kapaettu
K
Satyamoorthy
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India. Electronic address: girish.katta@manipal.edu.
Katta Mohan
KM
Girisha
D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D016537:Gangliosidosis, GM1 / Q000235:genetics*; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D001616:beta-Galactosidase / Q000235:genetics*
C061901:GLB1 protein, human; D001616:beta-Galactosidase
GLB1 gene; GM1 gangliosidosis; India; Mutation