Researchers at the National Institutes of Health, led by Dr. Natalie Shaw, have found that a toxic protein made by the body called DUX4 may be the cause of two very different rare genetic disorders. For patients who have facioscapulohumeral muscular dystrophy (FSHD), or a rare facial malformation called arhinia, this research discovery may eventually lead to therapies that can help people with these rare diseases.  Their latest publication is the subject of a February 17, 2023 NIH press release; the full paper can be found at DOI: 10.1126/sciadv.abq7744.

The NIEHS researchers have collaborated with researchers at the University of Iowa Carver College of Medicine, Iowa City, which is also the home of a Wellstone Muscular Dystrophy Specialized Research Center (MDSRC). The Centers of Excellence program in muscular dystrophy research was established by NIH in 2003, in honor of the late Senator Paul D. Wellstone of Minnesota. The six Wellstone Centers are funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD), and the National Heart, Lung, and Blood Institute (NHLBI). The Iowa Wellstone Center is funded by NINDS.

Aaron Stence in our UIHC Molecular Pathology Laboratory and Steve Moore, UIHC neuropathologist, have provided diagnostic laboratory testing and Wellstone MDSRC laboratory cell culture and muscle biopsy support to Dr. Natalie Shaw since 2016 in her ground breaking studies of Bosma arhinia microphthalmia syndrome first published in 2017.(1)  These studies have determined that FSHD type 2 and arhinia are allelic variants of rare genetic diseases linked to dominant mutations in SMCHD1.(1-5)  The contributions of Iowa’s Molecular Pathology Laboratory have drawn on our extensive diagnostic testing expertise in FSHD(6,7) to facilitate Dr. Shaw’s basic science research program.

Graphic from reference #7.

References

1. Shaw ND et al., Mutations in SMCHD1 are associated with isolated arhinia, Bosma arhinia microphthalmia syndrome, and facioscapulohumeral muscular dystrophy type 2.  Nat Genet 49:238-248, 2017. DOI: 10.1038/ng.3743
2. Mul N, Lemmers RJLF et al., FSHD type 2 and Bosma arhinia microphthalmia syndrome: two faces of the same mutation. Neurology 91(6):e562-e570, 2018. DOI: 10.1212/WNL.0000000000005958
3. Lemmers RJLF et al., SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localization of variants in the ATPase domain.  Journal of Medical Genetics 56:693-700, 2019. DOI: 10.1136/jmedgenet-2019-106168
4. Mohassel P et al., A cross-sectional, neuromuscular phenotyping study of arhinia patients with SMCHD1 variants.  Neurology 98:e1384-e1396, 2022. DOI: 10.1212/WNL.0000000000200032
5. Inoue K et al., DUX4 double whammy: the transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose. Science Advances 9(7), eabq7744, 17 February 2023. DOI: 10.1126/sciadv.abq7744
6. Rieken A et al., CLIA laboratory genetic testing of facioscapulohumeral muscular dystrophy: a retrospective analysis.  Neurology 96(7):e1054-e1062; 16 February 2021. DOI: 10.1212/WNL.0000000000011412
7. Stence AA et al., Validation of optical genome mapping for the molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD).  J Molecular Diagnostics 23:1506-1514, 2021. DOI: 10.1016/j.jmoldx.2021.07.021