학술논문
UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly
Document Type
Original Paper
Author
Schnur, Rhonda E.; Yousaf, Sairah; Liu, James; Chung, Wendy K.; Rhodes, Lindsay; Marble, Michael; Zambrano, Regina M.; Sobreira, Nara; Jayakar, Parul; Pierpont, Mary Ella; Schultz, Matthew J.; Pichurin, Pavel N.; Olson, Rory J.; Graham, Gail E.; Osmond, Matthew; Contreras-García, Gustavo A.; Campo-Neira, Karina A.; Peñaloza-Mantilla, Camilo A.; Flage, Mark; Kuppa, Srikar; Navarro, Karina; Sacoto, Maria J. Guillen; Wentzensen, Ingrid M.; Scarano, Maria I.; Juusola, Jane; Prada, Carlos E.; Hufnagel, Robert B.
Source
Genetics in Medicine: Official journal of the American College of Medical Genetics and Genomics. 23(9):1624-1635
Subject
Language
English
ISSN
1098-3600
1530-0366
1530-0366
Abstract
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.