This report describes intellectual disability, autosomal recessive 37; an alternative designation of this disease is 'mental retardation, autosomal recessive 37' (MRT37). The human gene implicated in this disease is Ankyrin 3 (ANK3), which encodes multiple isoforms of a membrane-cytoskeleton linker. There are two similar genes in humans, ANK1 and ANK2. There are two orthologous genes in Drosophila: Dmel\Ank, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated, and Dmel\Ank2, for which classical loss-of-function alleles, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.
A UAS construct of the wild-tpe human Hsap\ANK3 gene has been introduced into flies, but has not been characterized.
Animals carrying loss-of-function mutations of Dmel\Ank2 typically die in late larval/early pupal stages. Larval phenotypes include neuroanatomy defective and neurophysiology defective; defects of neuromuscular junctions are observed. Pan-neuronal expression of an RNAi construct targeting Dmel\Ank2 results in a memory defective phenotype in adults. Physical interactions of the Dmel\Ank2 protein product have been described; see below and in the FlyBase gene report for Ank2.
[updated Mar. 2020 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 37; MRT37](https://omim.org/entry/615493)
[ANKYRIN 3; ANK3](https://omim.org/entry/600465)
A heterozygous disruption of all isoforms of the ANK3 gene results in a cognitive deficit, sleeping problems, autism, severe ADHD and aggressive behavior. The first reported familial ANK3 mutation, a homozygous frameshift mutation affecting the longest isoform of ANK3, causes recessive ID, epilepsy, sleeping disorder, hypotonia, spasticity, hyperactivity and aggressive behavior. [Iqbal et al., 2013; pubmed:23390136]
Association of MRT37 with the ANK3 gene is based on two assessments: one consanguineous family carrying a frameshift mutation in the ANK3 gene that affects the longest isoform of the gene, and an unrelated individual with a balanced translocation with a heterozygous break in the ANK3 gene that disrupts all isoforms. Thus, in both cases, some gene function is retained. In the case of the consanguineous family, the disease segregates as an autosomal recessive. [Iqbal et al., 2013; pubmed:23390136]
The ANK3 gene encodes ankyrin-3 protein, a membrane-cytoskeleton linker. Alternatively spliced isoforms show variable patterns of tissue specificity. In neurons, ankyrin-3 may participate in the maintenance/targeting of ion channels and cell adhesion molecules at the nodes of Ranvier and axonal initial segments. [Kordeli et al., 1995; pubmed:7836469]
Ortholog of human genes ANK1, ANK2 and ANK3 (2 Drosophila to 3 human). Dmel\Ank2 shares 43% identity and 61% similarity with Hsap\ANK1; it shares 30-33% identity and 43-46% similarity with Hsap\ANK2 and Hsap\ANK3. Most isoforms of Dmel\Ank2 are much longer than any of the human genes (and than Dmel\Ank); within the ankyrin repeat domain at the amino end of the proteins it shares 59-61% identity and 75-77% similarity with three human genes.
