Absence of the nose, or arhinia, appears to be caused in part by the same gene that contributes to a rare form of muscular dystrophy, according to a new study appearing in Nature Genetics.

The findings, by an international consortium of more than 70 researchers, are the first report of a genetic cause for arhinia. This extremely rare condition has been observed in about 100 people worldwide, and is often accompanied by abnormally small eyes and reproductive failure, a triad termed Bosma arhinia microphthalmia syndrome (BAM). The researchers found that mutations in the gene SMCHD1 underlie isolated arhinia and BAM, conditions that are strikingly distinct from another disorder, fascioscapulohumeral muscular dystrophy 2 (FSHD2), reported previously to be caused by SMCHD1 mutations. 

According to geneticist Erica Davis, Ph.D., at the Duke Center for Human Disease Modeling, a senior author on the study, this finding is of broad interest to the scientific and medical community “because it has provided us with another example in which mutations in one gene can give rise to two different conditions.” The results also offer important information for patients affected with arhinia. “Although these individuals are few,” Davis said, “it is certainly meaningful for them to know the genetic etiology of their condition.” 

Davis was among a multidisciplinary team of scientists from the U.S. and in Japan, Switzerland, Italy, Mexico, Columbia, Germany, Belgium, France, and the U.K. involved in the study. Researchers first sequenced the exomes of 40 arhinia patients. Exomes are the protein-coding portions of the genome. They found that 84 percent of these patients harbored a mutation in a relatively narrow region of SMCHD1, a gene whose large protein product is known to bind DNA and regulate other genes. 

Fascioscapulohumeral muscular dystrophy 2 involves defects in the make-up of muscle, skeletal muscle weakness, and muscle cell death. This disorder was previously shown to be caused in part by mutations in SMCHD1, in combination with another region of the genome which displays a distinctive pattern of methylation, a type of modification of the DNA molecule. 

The researchers observed the same reduced methylation pattern in the arhinia patients as that in FSHD2. Davis called the overlap in methylation patterns “quite unexpected,” noting that it constituted one line of evidence in favor of a loss-of-function genetic effect in both disorders.

The primary contribution of the Duke team was to assess further the functional consequences of SMCHD1 mutations. Davis and her colleagues -- Zachary Kupchinsky, Jason Willer, and Nicholas Katsanis, Ph.D. -- used a zebrafish model. Although these fish do not have noses, the researchers evaluated facial cartilage patterning as a surrogate feature. They found that when they disrupted the zebrafish version of SMCHD1, the width of the nasal cavity decreased, and other cartilaginous structures were disrupted. 

Additionally, the genetically altered fish had smaller eyes and other irregular features compared to normal fish, indicating symptoms of Bosma arhinia microphthalmia syndrome. Zebrafish lack the other gene known to be necessary for fascioscapulohumeral muscular dystrophy in humans, perhaps explaining why they did not display symptoms of that disorder. 

Future studies will be needed to uncover the molecular mechanisms by which the newly-identified genetic mutations contribute to arhinia. Additionally, it remains unclear how the mutations give rise to both a severe craniofacial disorder as well as a rare muscle disease. 

Michael Talkowski (Massachusetts General Hospital, Harvard Medical School, and the Broad Institute of MIT and Harvard), David FitzPatrick (University of Edinburgh), and Davis are corresponding authors for this study. Co-first authors are Natalie Shaw of Massachusetts General Hospital and the National Institute of Environmental Health Sciences, and Harrison Brand of Massachusetts General Hospital, Harvard Medical School, and the Broad Institute of MIT and Harvard. 

Funding for this study was provided by the National Institutes of Health (R00MH095867, P01GM061354, T32HD007396, R01HD081256, P50HD028138, K23HD073304-02, 1SI2ES025429-01, R01AR062587, and U54-NS053672), the March of Dimes, the Massachusetts General Hospital Research Scholars program, the Medical Research Council, the German Research Foundation, the Berlin Institute of Health, and the University of Edinburgh Institute of Genomics and Molecular Medicine Translational Initiative Fund.