This report describes intellectual disability, autosomal recessive 2, which is one of an extensive series of diseases classified as intellectual disability, autosomal recessive. An alternative designation of this disease is 'mental retardation, autosomal recessive 2' (MRT2). The human gene implicated in this disease is CRBN, which encodes a substrate recognition component of a DCX/CUL4 E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. There is a single Drosophila ortholog, ohgt, for which RNAi-targeting constructs, an allele caused by insertional mutagenesis, a loss-of-function mutation caused by imprecise excision of a TE insertion, and an amorphic allele created by targeted recombination have been generated.
A UAS construct of a tagged human Hsap\CRBN gene has been introduced into flies, but has not been characterized in the context of this human disease model.
Animals homozygous for loss-of-function mutations of Dmel\ohgt exhibit decreased probability of neurotransmission release, as assayed for larval neuromuscular junction synapses. A wild-type copy of the fly gene rescues this phenotype, but a gene carrying a nonsense mutation comparable to one implicated in MRT2 does not. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G552* in the fly ohgt gene (comparable to R419* in the human CRBN gene). A single physical interaction has been described for Dmel\ohgt; see below and in the ohgt gene report.
[updated June 2018 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).
[INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 2; MRT2](https://omim.org/entry/607417)
[CEREBLON; CRBN](https://omim.org/entry/609262)
Two pedigrees extensively characterized: one with individuals exhibiting mild nonsyndromic intellectual disability, the other with individuals exhibiting severe intellectual disability, self-mutilating behavior, and seizures. [from MIM:607417; 2018.06.19]
Autosomal recessive mental retardation-2 (MRT2) is caused by homozygous mutation in the gene encoding cereblon (CRBN). [from MIM:607417; 2018.06.19]
CRBN encodes a substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins; normal degradation of the targeted regulatory proteins is required for normal limb outgrowth. In mammals, the CRBN protein product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. [Gene Cards, CRBN; 2018.06.19]
CRBN is a substrate receptor within the CRL4 E3-ubiquitin-ligase complex; it has been identified as a thalidomide-binding protein. [from MIM:609262; 2018.06.19]
One to one (1 human to 1 Drosophila).
High-scoring ortholog of human CRBN (1 Drosophila to 1 human); Dmel\ohgt shares 28% identity and 47% similarity with the human gene.
