Identification of a new genetic disorder affecting the brain and skull



An infant was born with severe defects of the brain and craniofacial skeleton with no known cause, leading the family to turn to the NIH Undiagnosed Diseases Program (UDP). Using genomic analyses of the family, UDP investigators discovered a mutation in the patient’s OTUD5 gene and identified several other individuals affected by the same mutation. The OTUD5 gene is involved in ubiquitylation, a process that often plays a role in determining the fate of cells during early stages of development, but it was unknown how malfunction of this gene could produce this group of severe developmental defects.


Using their expertise in ubiquitylation and embryonic development, researchers led by IRP Stadtman Investigator Achim Werner, Ph.D., found that the OTUD5 gene promotes normal development of the cells that will become the brain and the tissue making up the skull. Furthermore, they discovered that OTUD5 does this by preventing several DNA-remodeling proteins from being destroyed. However, when the gene is mutated, the DNA-remodeling proteins are destroyed and the cells do not have the correct instructions to develop normally, leading to the defects seen in patients with the OTUD5 mutation.


The study of rare diseases can improve our understanding of common diseases, as well as provide exciting discoveries about previously unstudied gene functions. The realization that OTUD5 elicits its effects through multiple DNA-remodeling proteins revealed a new principle of cellular signaling during early embryonic development, which can now be investigated to determine its role in other developmental syndromes. In addition, the identification of the OTUD5 mutation and the developmental syndrome it causes provided the patients’ families with a definitive diagnosis, which was not possible before the discovery was made.


Beck DB, Basar MA, Asmar AJ, Thompson JJ, Oda H, Uehara DT, Saida K, Pajusalu S, Talvik I, D’Souza P, Bodurtha J, My W, Barañano KW, Miyake N, Wang R, Kempers M, Tamada T, Nishimura Y, Okada S, Kosho T, Dale R, Mitra A, Macnamara E, Undiagnosed Diseases Network; Matsumoto N, Inawaza J, Walkiewicz M, Õunap K, Tifft CJ, Aksentijevich I, Kastner DL, Rocha PP, Werner A. (2021). Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. Sci Adv. Jan 20;7(4):eabe2116. doi: 10.1126/sciadv.abe2116.

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This page was last updated on Thursday, June 8, 2023