Genetic Analysis of Neuroligin 4Y Gene in Autism Population of India

Rajat Hegde; Smita Hegde; Suyamindra S. Kulkarni; Aditya Pandurangi; Pramod B. Gai; Kusal K. Das

doi:10.1055/s-0041-1736236

Global Medical Genetics, Table of Contents

CC BY 4.0 · Glob Med Genet 2022; 09(01): 018-022
DOI: 10.1055/s-0041-1736236

Original Article

Genetic Analysis of Neuroligin 4Y Gene in Autism Population of India

Rajat Hegde

¹Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India

²Karnataka Institute for DNA Research, Dharwad, Karnataka, India

,

Smita Hegde

²Karnataka Institute for DNA Research, Dharwad, Karnataka, India

³Human Genetics Laboratory, Department of Anatomy, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India

,

Suyamindra S. Kulkarni

²Karnataka Institute for DNA Research, Dharwad, Karnataka, India

,

Aditya Pandurangi

⁴Department of Psychiatry, Dharwad Institute of Mental Health and Neurosciences, Dharwad, Karnataka, India

,

Pramod B. Gai

²Karnataka Institute for DNA Research, Dharwad, Karnataka, India

,

Kusal K. Das

¹Laboratory of Vascular Physiology and Medicine, Department of Physiology, Shri B.M. Patil Medical College, Hospital and Research Centre, BLDE (Deemed to be University), Vijayapura, Karnataka, India

› Author Affiliations

Abstract

Background Autism is one of the most complex, heterogeneous neurological disorders. It is characterized mainly by abnormal communication, impaired social interaction, and restricted behaviors. Prevalence of autism is not clear in Indian population.

Aim The present study hypothesized that Y chromosome plays role in sex bias of autism in Indian autistic population. To investigate our hypothesis, we underwent genetic analysis of neuroligin 4Y [NLGN4Y] gene by sequencing 85 male autistic children after screening large population of 1,870 mentally ill children from North Karnataka region of India.

Result Detailed sequencing of the single targeted gene revealed nine variants including, one novel missense mutation and eight synonymous variants; this accounts for 88.9% of synonymous variants. A single novel missense mutation is predicted to be nonpathogenic on the functions of neuroligin4Y protein but it slightly affects the local configuration by altering the original structure of a protein by changing charge and size of amino acid.

Conclusion Probably NLGN4Y gene may not be the risk factor for autism in male children in Indian autistic population. Functional analysis was an important limitation of our study. Therefore, detailed functional analysis is necessary to determine the exact role of novel missense mutation of neuroligin 4Y [NLGN4Y] gene especially in the male predominance of autism in Indian autistic population.

Keywords

autism - neuroligin 4Y - India - novel missense mutation - male predominance

Full Text

References

References
1 Spence SJ. The genetics of autism. Semin Pediatr Neurol 2004; 11 (03) 196-204
2 Nguyen TA, Lehr AW, Roche KW. Neuroligins and neurodevelopmental disorders: X-linked genetics. Front Synaptic Neurosci 2020; 12: 33
3 Boucard AA, Chubykin AA, Comoletti D, Taylor P, Südhof TC. A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to α- and β-neurexins. Neuron 2005; 48 (02) 229-236
4 Nguyen TA, Wu K, Pandey S. et al. A cluster of autism-associated variants on X-linked NLGN4X functionally resemble NLGN4Y. Neuron 2020; 106 (05) 759-768.e7
5 Bemben MA, Shipman SL, Nicoll RA, Roche KW. The cellular and molecular landscape of neuroligins. Trends Neurosci 2015; 38 (08) 496-505
6 Jeong J, Paskus JD, Roche KW. Posttranslational modifications of neuroligins regulate neuronal and glial signaling. Curr Opin Neurobiol 2017; 45: 130-138
7 Ross JL, Bloy L, Roberts TPL. et al. Y chromosome gene copy number and lack of autism phenotype in a male with an isodicentric Y chromosome and absent NLGN4Y expression. Am J Med Genet B Neuropsychiatr Genet 2019; 180 (07) 471-482
8 Venselaar H, Te Beek TAH, Kuipers RKP, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 2010; 11 (01) 548
9 Kanner L. Follow-up study of eleven autistic children originally reported in 1943. J Autism Child Schizophr 1971; 1 (02) 119-145
10 Lawson-Yuen A, Saldivar JS, Sommer S, Picker J. Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet 2008; 16 (05) 614-618
11 Yan J, Oliveira G, Coutinho A. et al. Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry 2005; 10 (04) 329-332
12 Kent R, Simonoff E. Prevalence of Anxiety in Autism Spectrum Disorders. Anxiety in Children and Adolescents with Autism Spectrum Disorder: Evidence-Based Assessment and Treatment. Elsevier Inc.; Academic Press; United States: 2017: 5-32
13 Volaki K, Pampanos A, Kitsiou-Tzeli S. et al. Mutation screening in the Greek population and evaluation of NLGN3 and NLGN4X genes causal factors for autism. Psychiatr Genet 2013; 23 (05) 198-203
14 Ross JL, Tartaglia N, Merry DE, Dalva M, Zinn AR. Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features. Genes Brain Behav 2015; 14 (02) 137-144
15 Ylisaukko-oja T, Rehnström K, Auranen M. et al. Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet 2005; 13 (12) 1285-1292
16 Sand P, Langguth B, Hajak G. et al. Screening for neuroligin 4 (NLGN4) truncating and transmembrane domain mutations in schizophrenia. Schizophr Res 2006; 82 (2-3): 277-278
17 Serajee FJ, Mahbubul Huq AH. Association of Y chromosome haplotypes with autism. J Child Neurol 2009; 24 (10) 1258-1261
18 Yan J, Feng J, Schroer R. et al. Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr Genet 2008; 18 (04) 204-207