Functional loss of ubiquitin-specific protease 14 may lead to a novel distal arthrogryposis phenotype.

Autor: Turgut GT; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey., Altunoglu U; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.; Department of Medical Genetics, Koç University School of Medicine (KUSoM), Istanbul, Turkey., Sivrikoz TS; Perinatology Unit, Department of Obstetrics and Gynecology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey., Toksoy G; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey., Kalaycı T; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey., Avcı Ş; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.; Department of Medical Genetics, Koç University School of Medicine (KUSoM), Istanbul, Turkey., Karaman B; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.; Department of Pediatric Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Turkey., Gulec C; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey., Başaran S; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey., Sayın GY; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey., Kayserili H; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.; Department of Medical Genetics, Koç University School of Medicine (KUSoM), Istanbul, Turkey., Uyguner ZO; Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2022 Apr; Vol. 101 (4), pp. 421-428. Date of Electronic Publication: 2022 Jan 31.
DOI: 10.1111/cge.14117
Abstrakt: Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features.
(© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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