MODY breakthroughJune 5, 2018
In a path-breaking study, researchers have identified a new variant of monogenic form of diabetes in India.
Monogenic diabetes, which is caused due to a single gene defect, is one of the many forms of diabetes increasingly being discovered nowadays. The most common form of monogenic diabetes is Maturity Onset Diabetes of the Young (MODY) which, like Type 1 diabetes, affects young people or children. It is now known that there are 14 different forms of MODY, each with its own unique clinical characteristics.
In the largest such study ever carried out in the country, researchers have come out with evidence for additional MODY relevant genes in South India apart from the most frequently mutated.
The study was conducted by Dr V. Mohan and Dr Radha Venkatesan from Chennai-based Madras Diabetes Research Foundation (MDRF) in collaboration with Dr Andrew S. Peterson, Dr Somasekar, Seshagiri and Dr Thong T. Nguyen from Genentech, California and Dr Ramprasad and Sam Santhosh at MedGenome, India, and was based on a comprehensive genomic analysis of 289 individuals from India.
The study included 152 clinically diagnosed MODY cases and 137 normal glucose tolerance subjects (NGT). None of the NGT subjects showed any genetic variants associated with MODY.
Among the 152 clinically diagnosed MODY subjects, MODY 3 was found to be the most prevalent, which is in keeping with studies in Europe and UK.
However, surprisingly, the second most common MODY detected in India was MODY 12, (ABCC8 MODY). Moreover, 13 of the 14 known forms of MODY were detected in Indians.
Patients with MODY are often wrongly labelled as having Type 1 diabetes and advised to have lifelong insulin injections. MODY can only be diagnosed by doing genetic testing, according to the researchers, and genetic diagnosis of the disorder can transform patient management. according the researchers.
Dr Shashank Joshi
“Identification of the single gene that is responsible for MODY is certainly a breakthrough. But unless the discovery of NKX6 contributes to better disease management protocol, it doesn’t have much relevance to the treatment regime”
“Once the diagnosis of MODY is confirmed, in most forms of MODY, insulin injections can be completely stopped and these patients can be treated with a very inexpensive sulphonylurea tablet which has been used for decades for treating diabetes,” commented Dr V Mohan, director, Mohan’s Diabetes Research Foundation (MDRF), who led the study.
Individuals with mutations in GCK do not ordinarily need pharmacological treatment whereas those with mutations in KCNJ11 or ABCC8 are often best managed with high dose sulfonylureas rather than with insulin, they said in the study published in BMC Medical Genetics journal. Patients with mutations in HNF1A or HNF4A benefit from treatment with low dose sulfonylureas, the researchers added.
A recent study on diabetes in youth reported that MODY was misdiagnosed in 36% of the cases as Type 1 and in 51% of the cases as Type 2, highlighting the need for molecular genetic diagnosis among young diabetic patients.
However, what made the study more interesting was the discovery of a novel MODY gene, NKX6-1.
“This is the first time in the world the NKX6-1 gene mutation has been described as a novel form of MODY,’’ explained Dr Radha Venkatesan, co-author of the study and head of Genomics at MDRF.
Functional assessment of the NKX6-1 variant showed that the gene was functionally impaired, confirming that it was indeed a cause of MODY.
Further studies, however, are required to see whether the newly discovered MODY variant is unique to Indians or if it is present in other ethnic groups as well, she added.
Experts in the field of diabetology hailed the discovery of the new gene.
“Identification of the single gene that is responsible for MODY is certainly a breakthrough,’’ said Dr Shashank Joshi, leading endocrinologist from Mumbai.
Dr Joshi, however, went on to add that unless the discovery of NKX6 contributes to better disease management protocol, it doesn’t hold much relevance to the treatment regime.
MODY is rare in the country. All the patients undergoing treatment for MODY are not on insulin. As of now, endocrinologists depend on definitive diagnostic tools such as C-peptide testing to clinically assess how much insulin a person is producing. Generally, supplementary insulin is prescribed only after such evaluations.
Still, further research based on this discovery has the potential to lead to better outcome of treatment, he said.
NKX6-1: New MODY gene in South India
The NKX6-1 gene mutation has been identified as a pathogenic variant among those suffering from maturity-onset diabetes of the young (MODY) in South India.
Assessment of the NKX6-1 variant showed that they were functionally impaired, confirming that they were indeed the cause of MODY in carriers.
For each of the two NKX6–1 variants, and the functionally impaired control mutant, a new Indian study found significant differences in gene expression between cells expressing the variant as compared to cells expressing wild type NKX6–1.
“This is the first time in the world, the NKX6-1 gene mutation has been described as a novel form of MODY,’’ explained Dr Radha Venkatesan, co-author of the study and head of Genomics at MDRF.
The study, conducted by MDRF in association with Genentech, found MODY 3 (HNF1A) to be most frequently mutated variant at 7.2%, followed by MODY 12 (ABCC8) at 3.3%.
In addition to the NKX6-1 MODY gene, the study identified variants in RFX6, WFS1 and AKT2 that may contribute to development of treatments for MODY.