UBA2 Variants Underlie a Recognizable Syndrome with Variable Aplasia Cutis Congenita and Ectrodactyly

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2021 May 27

PMID 34040189

Citations 5

Authors

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-Garcia

Karina A Campo-Neira

Camilo A Penaloza-Mantilla

Mark Flage

Srikar Kuppa

Karina Navarro

Maria J Guillen Sacoto

Ingrid M Wentzensen

Maria I Scarano

Jane Juusola

Carlos E Prada

Robert B Hufnagel

Affiliations

Soon will be listed here.

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.

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