This report describes intellectual disability, autosomal dominant 48, a subtype of intellectual disability, autosomal dominant. The human gene implicated is RAC1, which encodes a Rho GTPase. There are two high-scoring fly orthologs, Dmel\Rac1 and Dmel\Rac2; only Dmel\Rac1 has been analyzed in the context of this disease model. Multiple genetic reagent, including loss of function alleles, RNAi-targeting constructs, alleles caused by insertional mutagenesis, and dominant negative mutations, have been generated for Dmel\Rac1.
The human Hsap\RAC1 gene has been introduced into flies, but has not been used to model intellectual disability, autosomal dominant 48.
A variant analogous to the disease-implicated Y64D mutation in the human RAC1 gene has been introduced into Dmel\Rac1; see the 'Disease-Implicated Variants table below. Isolated and cultured Drosophila embryonic neurons in which this variant has been expressed exhibit shorter axonal length with increased filopodial extensions along the axonal shaft. When driven pan-neuronally, expression of mutant Dmel\Rac1 results in frequent defects of axonal organization and fasciculation in the embryonic central nervous system. When driven in larval multidendritic class IV neurons, expression of Dmel\Rac1 bearing the Y64D mutation results in significant changes to the morphology of these neurons.
[updated Jan. 2023 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 DOMINANT 48; MRD48](https://omim.org/entry/617751)
[RAS-RELATED C3 BOTULINUM TOXIN SUBSTRATE 1; RAC1](https://omim.org/entry/602048)
Eight patients with missense mutations in the switch II region of RAC1 display variable combinations of developmental delay, intellectual disability, brain anomalies such as polymicrogyria and cardiovascular defects with normocephaly or relatively milder micro- or macrocephaly (Banka, et al. 2022, FBrf0255353).
Seven unrelated male patients displayed global developmental delay and moderate to severe intellectual disability; phenotypes were highly variable. Other neurologic features included poor feeding, hypotonia (in 4 patients), seizures (3), behavioral problems (3), and stereotypical movements (3). Four patients had microcephaly, and 2 had macrocephaly (Reijinders, et al. 2017 pubmed:28886345). [from MIM:617751; 2023.01.18]
Intellectual disability, autosomal dominant 48 is caused by heterozygous mutation in the RAC1 gene on chromosome 7p22. [from MIM:617751; 2023.01.18]
The RAC1 gene encodes a RHO GTPase involved in modulation of the cytoskeleton which plays a role in multiple cellular functions, including phagocytosis, mesenchymal-like migration, neuronal polarization, axonal growth, and differentiation of multiple cell types. RAC1 is also involved in cellular growth and cell-cycle regulation (summary by Reijnders et al., 2017, pubmed:28886345). [from MIM:602048; 2023.01.17]
High-scoring ortholog of human RAC1 and RAC2; moderate scoring ortholog of human RAC3 (2 Drosophila to 3 human).
