UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly

Rhonda E. Schnur, Sairah Yousaf, James Liu, Wendy K. Chung, Lindsay Rhodes, Michael Marble, Regina M. Zambrano, Nara Sobreira, Parul Jayakar, Mary Ella Pierpont, Matthew J. Schultz, Pavel N. Pichurin, Rory J. Olson, Gail E. Graham, Matthew Osmond, Gustavo A. Contreras-García, Karina A. Campo-Neira, Camilo A. Peñaloza-Mantilla, Mark Flage, Srikar KuppaKarina Navarro, Maria J.Guillen Sacoto, Ingrid M. Wentzensen, Maria I. Scarano, Jane Juusola, Carlos E. Prada, Robert B. Hufnagel

Research output: Contribution to journalArticlepeer-review


Purpose: The human chromosome 19q13.11 deletion syndrome is associated with a variable phenotype that includes aplasia cutis congenita (ACC) and ectrodactyly as specific features. UBA2 (ubiquitin-like modifier-activating enzyme 2) lies adjacent to the minimal deletion overlap region. We aimed to define the UBA2-related phenotypic spectrum in humans and zebrafish due to sequence variants and to establish the mechanism of disease. Methods: Exome sequencing was used to detect UBA2 sequence variants in 16 subjects in 7 unrelated families. uba2 loss of function was modeled in zebrafish. Effects of human missense variants were assessed in zebrafish rescue experiments. Results: Seven human UBA2 loss-of-function and missense sequence variants were detected. UBA2-phenotypes included ACC, ectrodactyly, neurodevelopmental abnormalities, ectodermal, skeletal, craniofacial, cardiac, renal, and genital anomalies. uba2 was expressed in zebrafish eye, brain, and pectoral fins; uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins. uba2-mRNAs with human missense variants failed to rescue nullizygous zebrafish phenotypes. Conclusion: UBA2 variants cause a recognizable syndrome with a wide phenotypic spectrum. Our data suggest that loss of UBA2 function underlies the human UBA2 monogenic disorder and highlights the importance of SUMOylation in the development of affected tissues.

Original languageEnglish (US)
Pages (from-to)1624-1635
Number of pages12
JournalGenetics in Medicine
Issue number9
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Genetics(clinical)


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