This report describes intellectual disability, X-linked, syndromic, Turner type; an alternative designation of this disease is 'mental retardation, X-linked, syndromic, Turner type' (MRXST). MRXST exhibits X-linked dominant inheritance. The human gene implicated in this disease HUWE1, which is a ubiquitin protein ligase that marks target proteins for proteasomal degradation. There is a single Drosophila ortholog, Dmel\HUWE1, for which a single classical allele, multiple RNAi constructs, and an allele caused by insertional mutagenesis have been generated.
A UAS construct of the wild-type human Hsap\HUWE1 gene has been introduced into flies. Effects of increased levels of HUWE1 expression on the developing nervous system have been investigated.
Dmel\HUWE1 protein is ubiquitously expressed in the embryo and in larval tissues including the salivary gland and wing discs. An insertional mutation results in lethality; pan-neuronal expression of an RNAi construct results in semi-lethality. Dmel\HUWE1 is required for development of the larval salivary gland; decline in levels of Dmel\HUWE1 during the pupal allows activation of the JNK pathway that leads to the normal degeneration of the salivary gland during this stage. Physical and genetic interactions of Dmel\HUWE1 have been described; see the HUWE1 gene report.
[updated Jul. 2019 by FlyBase; FBrf0222196]
Intellectual disability is characterized by impairments in intellectual functioning and adaptive behavior; symptoms must be present before a child becomes 18 years old (http://medical-dictionary.thefreedictionary.com/mental+retardation; 2016.01.19).
Intellectual disability can be subdivided into syndromic forms, characterized by cognitive impairment accompanied by dysmorphic features, malformations or neurological abnormalities, and nonsyndromic forms, characterized by cognitive impairment without additional features (Basel-Vanagaite, 2008; DOI: 10.1002/9780470015902.a0021454).
Males show moderate to profound mental retardation with variable dysmorphic features; some heterozygous females exhibit mild mental retardation. [from MIM:300706; 2016.01.25]
MRXST is caused by mutation in the E3 ubiquitin-protein ligase HUWE1. Most pedigrees show an X-linked semi-dominant mode of inheritance. [from MIM:300706; 2016.01.25]
HUWE1 is an E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of multiple target proteins, including the anti-apoptotic protein Mcl1, p53 tumor suppressor, core histones, and DNA polymerase beta. [from UniProt:Q7Z6Z7; 2016.01.25]
The full name of the HUWE1 gene is 'HECT, UBA And WWE domain containing protein 1, E3 ubiquitin protein ligase.' [from HGNC:30892; 2016.01.25]
HUWE1-mediated ubiquitination typically marks specific target proteins for proteasomal degradation, but may play other regulatory roles, as well. [Gene Cards, HUWE1; 2017.06.19]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human HUWE1 (1 Drosophila to 1 human). Dmel\HUWE1 shares 32% identity and 45% similarity with the human gene.
