CCMB-led research identifies eight novel genes for male fertility

HYDERABAD: Researchers have identified eight novel genes in human male fertility and the mutations in these genes that cause infertility among men in India.

Dr. K Thangaraj's group at the CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, had been researching to understand the genetic causes of male infertility for the last two decades.

"We identified a total of eight genes (BRDT, CETN1, CATSPERD, GMCL1, SPATA6, TSSK4, TSKS, and ZNF318),that were not known earlier for their role in human male fertility.

"We have identified variations (mutations) in these genes that cause impaired sperm production leading to male infertility," said Dr Thangaraj, lead investigator of this study and presently director of the DBT-Centre for DNA Fingerprinting and Diagnostics, Hyderabad.

They have shown earlier that about 38 per cent males with infertility have specific regions missing or abnormalities in their Y chromosomes or mutations in their mitochondrial and autosomal genes.

Their new multi-institutional study focuses on the cause of infertility in the rest of the cases, which constitutes the majority of infertility-affected men, and has identified 8 novel genes that were defective in these men in India. The study has been recently published online in the journal Human Molecular Genetics.

Dr Sudhakar Digumarthi, lead author of the study, who was a PhD student of the CCMB and presently scientist at ICMR-National Institute for Research in Reproductive and Child Health in Mumbai, said they first sequenced all the essential regions of all genes (around 30,000 of them) using next generation sequencing in 47 well-characterised infertile men. They then validated the identified genetic changes in about 1,500 infertile men from different parts of India.

The researchers have characterised a mutation in one of the eight genes, Centrin 1 (CETN1), to understand how the mutation affects sperm production. They demonstrated the impact of CETN1 mutation in cellular models and found that the mutation arrests cell division, causing insufficient sperm production.

"This study should be a reminder to the society that half of the infertility cases are due to problems in men. And many of them are due to genes that come from the parents, often mothers, of these men. It is wrong to assume a couple cannot bear children because of only the woman's fertility," said Dr Thangaraj.

"The genetic causes established in this study could be used as potential diagnostic markers for male infertility, and development of improved management strategies for male infertility," CCMB Director, Dr Vinay Kumar Nandicoori, said.

Approximately, one out of every seven couples are infertile worldwide. Male infertility accounts for about 50 per cent of these cases. The cases range from defects in the male reproductive system, deficiencies in semen quality, and hormonal imbalance. Injuries, infections, chronic illness, lifestyle choices and genetic factors can all lead to infertility in males. The researchers, however, do not yet understand the details of how these parameters control fertility.

The institutes who were part of the study are Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, the Institute of Human Genetics, University Hospital Dusseldorf, the Heinrich-Heine-Universitat, Germany, the All India Institute of Medical Sciences, New Delhi, the CSIR-Central Drug Research Institute, Lucknow, the Institute of Reproductive Medicine, Kolkata, the Indian Institute of Science Education and Research (IISER), Berhampur, the Mamata Fertility Hospital, Secunderabad, and the DBT-Centre for DNA Fingerprinting and Diagnostics, Hyderabad.