NEW YORK (GenomeWeb) – Mutations in the SMCHD1 gene appear to be behind congenital arhinia, a condition in which a nose does not form, an international team of researchers has found.
Arhinia is rare, having been first reported in 1981 and in fewer than 50 patients since then. Because children with the condition don't have nasal airways, they often have to undergo tracheotomies and lack a sense of smell. Eye and reproductive issues have also been noted.
Researchers led by A*Star's Bruno Reversade uncovered SMCHD1 mutations within all 14 people with arhinia they investigated. While SMCHD1, which encodes an epigenetic regulator, hadn't been linked to craniofacial development before, it had been associated with adult-onset facioscapulohumeral muscular dystrophy type 2 (FSHD2). As they reported in Nature Genetics this week, the researchers found that gain-of-function SMCHD1 mutations appear to cause arhinia, while inactivating ones lead to FSHD2.
"This discovery is a fascinating example of how rare conditions can provide unsuspected insights into common diseases," Reversade said in a statement. "We will strive to translate these findings into potential therapeutics for FSHD."
He and his colleagues sequenced the whole exomes of six arhinia trios or quartets, and found de novo SMCHD1 mutations within all the cases. They uncovered SMCHD1 mutations in eight additional cases, through both exome and Sanger sequencing. All 14 SMCHD1 mutations were located within exons that encode the protein's ATPase domain or in an immediately adjacent region. Six mutations affected three adjacent amino acids, suggesting a potential mutational hotspot.
Through biochemical and animal model tests, the researchers found that SMCHD1 is expressed in the nasal cavities of developing mice, especially within immune olfactory sensory neurons. This, they noted, indicates that it has a role in early nasal development.
SMCHD1 haploinsufficiency, meanwhile, has been associated with FSHD2. In particular, FSHD2 occurs in people with loss-of-function SMCHD1 mutations and a mis-expression of the transcription factor DUX4. These SMCHD1 mutations — of which some 80 have been reported — are scattered throughout the protein.
Reversade and his colleagues suspected that the SMCHD1 mutations linked to arhinia and FSHD2 don't work in the same direction, as there are no reports of the conditions occurring together. In a crystal structure, they pinpointed the arhinia mutations to a region near the protein's ATPase domain, suggesting they could influence its function. In a series of assays, the researchers found that arhinia mutations increased the catalytic activity of SMCHD1 and, in a Xenopus model, that only tadpoles with over-expressed SMCHD1 had craniofacial anomalies. Together, this indicated to the researchers that the arhinia-linked SMCHD1 mutations amplify the protein's usual activity.
"Given that loss-of-function mutations in SMCHD1 are associated with FSHD2, [arhinia] and FSHD2 represent a rare example of different functional classes of mutations in the same gene leading to vastly different human disorders, in terms of the affected tissue and age of onset," the researchers wrote in their paper.
These findings also suggest potential therapeutic avenues for FSHD2, such as targeting the ATPase domain, they added.