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

Autor:	Schnur RE; Clinical Genomics Program, GeneDx, Gaithersburg, MD, USA. rschnur@genedx.com.; Division of Genetics, Department of Pediatrics, Cooper Medical School of Rowan University, Cooper University Health Care, Camden, NJ, USA. rschnur@genedx.com., Yousaf S; National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Liu J; National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Chung WK; Division of Clinical Genetics, Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA., Rhodes L; Clinical Genomics Program, GeneDx, Gaithersburg, MD, USA., Marble M; Department of Pediatrics, Division of Pediatric Genetics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA., Zambrano RM; Department of Pediatrics, Division of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA., Sobreira N; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA., Jayakar P; Division of Genetics and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA., Pierpont ME; Departments of Pediatrics and Ophthalmology, University of Minnesota Medical School, Minneapolis, MN, USA., Schultz MJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Pichurin PN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Olson RJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Graham GE; Division of Genetics, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada., Osmond M; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada., Contreras-García GA; Division de Genética Médica, Departamento de Pediatría-Hospital Universitario de Santander, Departamento de Ciencias Básicas, Grupo de Investigación en Genética Humana UIS, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia., Campo-Neira KA; Semillero de Investigación en Genética Humana SIGENH, Escuela de Medicina, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia., Peñaloza-Mantilla CA; Semillero de Investigación en Genética Humana SIGENH, Escuela de Medicina, Facultad de Salud, Universidad Industrial de Santander, Bucaramanga, Colombia., Flage M; National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Kuppa S; National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Navarro K; National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Sacoto MJG; Clinical Genomics Program, GeneDx, Gaithersburg, MD, USA., Wentzensen IM; Clinical Genomics Program, GeneDx, Gaithersburg, MD, USA., Scarano MI; Division of Genetics, Department of Pediatrics, Cooper Medical School of Rowan University, Cooper University Health Care, Camden, NJ, USA., Juusola J; Clinical Genomics Program, GeneDx, Gaithersburg, MD, USA., Prada CE; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Hufnagel RB; National Eye Institute, National Institutes of Health, Bethesda, MD, USA. robert.hufnagel@nih.gov.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Sep; Vol. 23 (9), pp. 1624-1635. Date of Electronic Publication: 2021 May 26.
DOI:	10.1038/s41436-021-01182-1
Abstrakt:	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. (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
Databáze:	MEDLINE
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