Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome.
Child, Preschool
Female
Genetic Diseases, X-Linked
/ complications
Genetic Predisposition to Disease
Heart Defects, Congenital
/ complications
Humans
Infant
Intellectual Disability
/ complications
Male
Pedigree
Skin Abnormalities
/ complications
Ubiquitin-Conjugating Enzymes
/ genetics
Urogenital Abnormalities
/ complications
UBE2A
clinical variation
genotype-phenotype correlations
intellectual disability Nascimento type
mutation spectrum
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
15
04
2020
revised:
11
05
2020
accepted:
13
05
2020
pubmed:
18
5
2020
medline:
10
7
2021
entrez:
17
5
2020
Statut:
ppublish
Résumé
UBE2A deficiency, that is, intellectual disability (ID) Nascimento type (MIM 300860), is an X-linked syndrome characterized by developmental delay, moderate to severe ID, seizures, dysmorphisms, skin anomalies, and urogenital malformations. Forty affected subjects have been reported thus far, with 31 cases having intragenic UBE2A variants. Here, we report on additional eight affected subjects from seven unrelated families who were found to be hemizygous for previously unreported UBE2A missense variants (p.Glu62Lys, p.Arg95Cys, p.Thr99Ala, and p.Arg135Trp) or small in-frame deletions (p.Val81_Ala83del, and p.Asp101del). A wide phenotypic spectrum was documented in these subjects, ranging from moderate ID associated with mild dysmorphisms to severe features including congenital heart defects (CHD), severe cognitive impairment, and pineal gland tumors. Four variants affected residues (Glu62, Arg95, Thr99 and Asp101) that contribute to stabilizing the structure of the E3 binding domain. The three-residue in-frame deletion, p.Val81_Ala83del, resulted from aberrant processing of the transcript. This variant and p.Arg135Trp mapped to regions of the protein located far from the E3 binding region, and caused variably accelerated protein degradation. By reviewing available clinical information, we revise the clinical and molecular profile of the disorder and document genotype-phenotype correlations. Pineal gland cysts/tumors, CHD and hypogammaglobulinemia emerge as recurrent features.
Substances chimiques
UBE2A protein, human
EC 2.3.2.23
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
172-178Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373-428. https://doi.org/10.1152/physrev.00027.2001.
Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20(11):1242-1253.
Roest HP, Baarends WM, de Wit J, et al. The ubiquitin-conjugating DNA repair enzyme HR6A is a maternal factor essential for early embryonic development in mice. Mol Cell Biol. 2004;24(12):5485-5495.
Koken MH, Smit EM, Jaspers-Dekker I, et al. Localization of two human homologs, HHR6A and HHR6B, of the yeast DNA repair gene RAD6 to chromosomes Xq24-q25 and 5q23-q31. Genomics. 1992;12:447-453.
Nascimento RMP, Otto PA, de Brouwer APM, Vianna-Morgante AM. UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a novel X-linked mental retardation syndrome. Am J Hum Genet. 2006;79:549-555.
Czeschik JC, Bauer P, Buiting K, et al. X-linked intellectual disability type Nascimento is a clinically distinct, probably underdiagnosed entity. Orphanet J Rare Dis. 2013;8:146.
Haddad DM, Vilain S, Vos M, et al. Mutations in the intellectual disability gene UBE2A cause neuronal dysfunction and impair parkin-dependent mitophagy. Mol Cell. 2013;50(6):831-843.
Stevenson RE, Chudley AE, Srivastava AK, Rodriguez J, Friez MJ, Schwartz CE. UBE2A-related X-linked intellectual disability. Clin Dysmorphol. 2019;28(1):1-6.
Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928-930.
Firth HV, Richards SM, Bevan AP, et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using Ensembl resources. Am J Hum Genet. 2009;84(4):524-533.
Budny B, Badura-Stronka M, Materna-Kiryluk A, et al. Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome. Clin Genet. 2010;77(6):541-551.
Hong JH, Kaustov L, Coyaud E, et al. KCMF1 (potassium channel modulatory factor 1) links RAD6 to UBR4 (ubiquitin N-recognin domain-containing E3 ligase and lysosome-mediated degradation). Mol Cell Proteomics. 2015;14:674-685.