‘Inter-familial marriages, best source to study recessive disorders’

A Pakistani professor from a Swiss university said consanguineous marriages were the best resource to study recessive disorders because it is easier to identify new genes in this population.

Muhammad Ansar from the University of Lausanne presented on the discovery of new recessive disease genes and therapeutic interventions at a seminar, held by the Korean Organization of Rare Disease (KORD) for rare disease patients in Seoul, Thursday. He was one of the two guest speakers from Swiss universities.

Participants of the event included rare disease organizations such as Korea’s Parkinson’s Disease Association.

Professor Ansar specifically introduced genetic treatments for rare retinal diseases like retinal pigmentosa (RP) and Cohen syndrome. He first identified novel variants and genes in patients and families with hereditary recessive disorders to improve genetic diagnoses.

He highlighted the importance of studying families with consanguineous marriages as the best resource to study recessive disorders because it is easier to identify new genes in this population.

According to Ansar, his research team studied a Pakistani family where two children had RP and found a mutation in the SLC6A6 gene which is responsible for transporting taurine, one of the most abundant amino acids in the retina.

Interestingly, he also noted that taurine is an essential component of cat diets which is linked not only to visual impairment but also cardiomyopathy. Through SLC6A6 gene knock out models in mice, retinitis pigmentosa was also confirmed.

Consequently, his research team was able to restore partial vision in the aforementioned children by administering taurine supplements. By investigating optical coherence tomography (OCT) images in the children before and after treatment, the researchers identified changes in the photoreceptor, with more cells becoming active after a 2-year treatment period. Similar treatment results were also observed when using taurine supplements to treat cardiomyopathy in patients with the SLC6A6 mutation.

Taking it one step further, Professor Ansar then showed the power of genetic diagnostics for a more complex disease like Cohen’s syndrome. Cohen’s syndrome is a very rare autosomal recessive genetic disorder with varied expression, characterized by obesity, intellectual disability, distinct craniofacial abnormalities and potential ocular dysfunction.

Likewise, he identified VPS13B as a recessive gene in this disorder but despite attempts to conduct gene deletion with antisense nucleotides and other gene replacement strategies, it was largely unsuccessful due to multiple symptoms and more complicated nature of the brain. Accordingly, Ansar’s team developed a high throughput assay to perform quick drug screening of FDA approved drugs as a more effective strategy to treat the symptoms of Cohen’s syndrome. As a result, this also helps to speed up pre-clinical trials for Cohen’s syndrome.

Ansar is also collaborating with Professor Woong Sun from Korea University on the drug development for Cohen’s syndrome where Professor Sun’s lab is assisting with drug testing on human brain organoid models to reduce the phenotype expression.

The two are working on screening the drugs that were successful on cell models on organoids, as some drugs which are successful in animal or cell models do not always have the same effect on humans.

Ansar also mentioned that he is receiving partial funding from a Seoul based pharmaceutical company called AriBio to develop a treatment for Cohen syndrome.

Meanwhile, his other work on rare diseases also include recessive cancers and infertility diseases like congenital hypogonadotropic hypogonadism (CHH) where his main goal is to discover new recessive genes to improve genetic diagnosis for rare diseases.

In the earlier session, Ph.D candidate of the Institute of Molecular and Clinical Ophthalmology Basel, Han Ji-hoon, presented his research outlining the process from DNA analysis to treatment for rare diseases.