A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy

Genet Med. 2021 May;23(5):900-908. doi: 10.1038/s41436-020-01071-z.

Min Ni ¹ ², Bushra Afroze ³, Chao Xing ⁴ ⁵ ⁶, Chunxiao Pan ⁷, Yanqiu Shao ⁶ ⁸, Ling Cai ⁶ ⁹, Brandi L Cantarel ⁵ ¹⁰, Jimin Pei ¹¹, Nick V Grishin ¹¹ ¹², Stacy Hewson ¹³, Devon Knight ¹⁴, Sonal Mahida ¹⁴, Donnice Michel ¹⁵, Mark Tarnopolsky ¹⁶, Annapurna Poduri ¹⁴, Alexander Rotenberg ¹⁴, Neal Sondheimer ¹³, Ralph J DeBerardinis ¹⁷ ¹⁸ ¹⁹ ²⁰

Affiliations

1 Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA. min.ni@utsouthwestern.edu.
2 Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA. min.ni@utsouthwestern.edu.
3 The Aga Khan University Hospital, Karachi, Pakistan.
4 Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA.
5 Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA.
6 Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.
7 Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.
8 Department of Statistical Science, Southern Methodist University, Dallas, TX, USA.
9 Quantitative Biomedical Research Center, UT Southwestern Medical Center, Dallas, TX, USA.
10 Bioinformatics Core Facility, UT Southwestern Medical Center, Dallas, TX, USA.
11 Department of Biophysics, UT Southwestern Medical Center, Dallas, TX, USA.
12 Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA.
13 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada.
14 Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
15 Children's Medical Center, Dallas, TX, USA.
16 Department Pediatrics and Medicine, McMaster University, Hamilton, Ontario, Canada.
17 Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA. ralph.deberardinis@utsouthwestern.edu.
18 Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA. ralph.deberardinis@utsouthwestern.edu.
19 Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA. ralph.deberardinis@utsouthwestern.edu.
20 Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA. ralph.deberardinis@utsouthwestern.edu.

PMID: 33473208 DOI: 10.1038/s41436-020-01071-z

Abstract

Purpose: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation.

Methods: Exome Sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts.

Results: The variant (c.344T>A; p.V115E) is rare and alters a conserved residue in UFSP2. Immunoblotting in patient-derived fibroblasts revealed reduced UFSP2 abundance and increased abundance of UFMylated targets, indicating the variant may impair de-UFMylation rather than UFMylation. Reconstituting patient-derived fibroblasts with wild-type UFSP2 reduced UFMylation marks. Analysis of UFSP2's structure indicated that variants observed in skeletal disorders localize to the catalytic domain, whereas V115 resides in an N-terminal domain possibly involved in substrate binding.

Conclusion: Different UFSP2 variants cause markedly different diseases, with homozygosity for V115E causing a severe syndrome of neurodevelopmental disability and epilepsy.

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