It is an extremely rare congenital disease with a very striking appearance: When children are born with no nose or with incompletely developed nasal structures, they have a condition called “arhinia”. Some also have eye anomalies – a combination that is known as Bosma syndrome. So far, the cause of this syndrome has been unclear, but an international collaboration led by Bernd Wollnik and his working group at the Institute of Human Genetics of the University Medical Center Göttingen has now uncovered that mutations in a specific gene lead to the failure of normal nose development in patients with arhinia and Bosma syndrome. At the same time, they have gained fascinating insights into the underlying mechanisms that act on the molecular level. And, remarkably, these new findings may also contribute to the development of novel treatment options for an entirely different congenital disorder. The results of their study have now been published in the renowned Nature Genetics journal.

The researchers investigated 14 patients with arhinia – so far less than 50 affected people have been described worldwide. Using the latest molecular genetic methods of next-generation sequencing, they analyzed the protein encoding regions of all 19.000 genes in patients. They discovered that all affected individuals carried a disease-causing mutation in the same gene. These mutations had newly occurred in the patients, i.e. children had not inherited them from their parents.

That mutations in this particular gene, SMCHD1, can have serious health implications had already been known – however, such genetic changes had so far only been described in relation to an entirely different disorder: SMCHD1 mutations had previously been identified in patients with a condition called facioscapulohumeral muscle dystrophy (FSHD) type 2, a muscular disease that may also involve the heart muscle. The current research study had therefore also been funded by the DFG CRC1002 “Modulatory units in heart failure” at Göttingen. “Our genetic studies now suggest that, depending on the type of mutation, changes in SMCHD1 can bring about entirely different conditions involving distinct organ systems and tissues” says Dr. Gökhan Yigit, who leads a junior research group at the Institute of Human Genetics and contributed significantly to the study.

To learn more about the consequences of the identified mutations and the function of the SMCHD1 protein, the different research teams based at Göttingen, Paris, Singapore and Melbourne and their collaboration partners performed biochemical assays and additional functional studies. They showed that the mutations in their patients increase the protein function – an effect which is contrary to that brought about by the mutations underlying FSHD as they lead to a disturbed SMCHD1 function. These findings are in line with the observation that the two conditions do not appear together, i.e. all patients who have been described to carry an SMCHD1 mutation have either a muscle disease or lack of nose. So it is the type and functional impact of the particular SMCHD1 mutation in a patient’s DNA that decides which of the condition will develop.

The extensive functional experiments did thus not only demonstrate that SMCHD1 is a key player in nose development, but they also shed further light on the general function of SMCHD1. This new understanding may contribute to the development of novel approaches for the treatment of FSHD type 2 muscle disease. “We have now learned how and by what mechanisms SMCHD1 protein function may be increased”, says Bernd Wollnik, director of the Institute of Human Genetics at Göttingen, “and this may form the basis for designing new, innovative therapeutic options for this severe muscle disease”.

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
Gordon CT, Xue S, Yigit G, Filali H, Chen K, […] Javed A, Blewitt ME, Amiel J, Wollnik B, Reversade B
Nat Genet. 2017 Jan 9. doi: 10.1038/ng.3765. [Epub ahead of print]