A gene mutation associated with a rare congenital condition involving the absence of a nose was identified. The international team of scientists also detected additional defects, generally affecting the eye and reproductive systems. Previous research has associated mutations at the level of the same genes, SMCHD1, with muscular dystrophy.
The study, published Jan. 9 in the journal Nature Genetics, united two lead authors who analyzed genomes of subjects with arhinia, then investigated the missing reproductive development in some of these subjects. Prior to this research only 80 cases had been reported with this condition during the last century, the scientists also contacted specialists from all over the world to identify patients that could possibly be subjected to testing.
Arhinia, Rare Genetic Condition
As part of the study, the team collected samples for genetic sequencing, screening the genes of 40 people who suffered from arhinia, as well as other 55 relatives from 38 families. The analyses carried out revealed rare single-nucleotide mutations in 84 percent of the subjects. The researchers were helped by specialists in 10 different countries, and the current research was conducted on 24 percent of the cases previously known, as well as other 21 newly diagnosed.
SMCHD1 is responsible for regulating the expression of other genes in the human body, such as FSHD2, which stands for fascioscapulohumeral muscular dystrophy 2, a disease that weakens muscles on the shoulders, face, and upper arms.
Before this study, there had been no reported cases of both ahrinia and FSHD2. However, the current research found two such families. In one of these families, the ahrinia patient had inherited an SMCHD1 mutation from his father, who lacked the condition but instead showed symptoms of FSHD2.
After this discovery, the researchers conducted a series of experiments as to get a better idea of the mechanism through which SMCHD1 mutations can cause arhinia. They blocked the expression of the SMCHD1 gene in zebrafish, which caused distorted facial cartilage, structural abnormalities of the neurons responsible for the reproductive system, and smaller eyes.
"SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes," noted the research.
However, a similar experiment conducted on mice showed that the mutation did not have any effect. The researchers attributed it to a varied series of possible mutations in arhinia, which could alter other health conditions, just as SMCHD1 affects FSHD2.
Arhinia And Its Genetic Implications
Arhinia patients were further subjected to analyses in order to take a better look at the methylation patterns caused by the disease and their consequences on the way the condition is manifested. The methylation patterns can suppress the transcription of a DNA portion. In the areas of the genome which are mutated in FSHD2, arhinia patients experienced identical methylation changes.
The research is the first of its magnitude, as it encompasses the largest number of cases diagnosed with the genetic mutation ever to have been subjected to research. Further studies could explore the directions in which this genetic mutation can manifest and the genomes it can affect.
