TY - JOUR
T1 - UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly
AU - Schnur, Rhonda E.
AU - Yousaf, Sairah
AU - Liu, James
AU - Chung, Wendy K.
AU - Rhodes, Lindsay
AU - Marble, Michael
AU - Zambrano, Regina M.
AU - Sobreira, Nara
AU - Jayakar, Parul
AU - Pierpont, Mary Ella
AU - Schultz, Matthew J.
AU - Pichurin, Pavel N.
AU - Olson, Rory J.
AU - Graham, Gail E.
AU - Osmond, Matthew
AU - Contreras-García, Gustavo A.
AU - Campo-Neira, Karina A.
AU - Peñaloza-Mantilla, Camilo A.
AU - Flage, Mark
AU - Kuppa, Srikar
AU - Navarro, Karina
AU - Sacoto, Maria J.Guillen
AU - Wentzensen, Ingrid M.
AU - Scarano, Maria I.
AU - Juusola, Jane
AU - Prada, Carlos E.
AU - Hufnagel, Robert B.
N1 - Funding Information:
We thank the individuals and families who participated in this project. We express our deepest gratitude to Mary Ella Pierpont for her valuable contribution and dedicate this report to her memory. W.K.C. received financial support from the JPB Foundation. N.S.’s work is supported by National Human Genome Research Institute (NHGRI) grant 1U54HG006542. We would like to thank Sunit Dutta (National Eye Institute, National Institutes of Health [NIH], Bethesda, MD) for assistance in establishing uba2 zebrafish knockout lines. We thank the zebrafish facility, Confocal, transmission electron microscopy, and microcomputed tomography mouse imaging facilities at NIH for their support and technical assistance. The research work carried out at NIH was supported by funds provided by National Eye Institute, NIH (Bethesda, MD).
Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85106467680&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106467680&partnerID=8YFLogxK
U2 - 10.1038/s41436-021-01182-1
DO - 10.1038/s41436-021-01182-1
M3 - Article
C2 - 34040189
AN - SCOPUS:85106467680
SN - 1098-3600
VL - 23
SP - 1624
EP - 1635
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
ER -