This report describes DYRK1A-related intellectual disability syndrome, which exhibits autosomal dominant inheritance. This disease is also described as a syndromic form of autosomal dominant intellectual disability. The human DYRK1A gene (dual specificity tyrosine phosphorylation regulated kinase 1A) plays a significant role in signaling pathways regulating cell proliferation and brain development. Deviation from diploidy for DYRK1A appears to be deleterious in either direction: the gene is located on chromosome 21 and is postulated to play a key role in the development of Down syndrome (see FBhh0001056).
There is a single high-scoring ortholog of DYRK1A in Drosophila, mnb, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\mnb, is also orthologous to a second human gene, DYRK1B.
The human DYRK1A gene has not been introduced into flies. A human frameshift/termination variant newly implicated in this disease has been investigated in flies, using the orthologous Drosophila gene. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): D401X in the fly mnb gene [corresponds to E396X (E358X, E387X) in the human DYRK1A gene].
As is the case for the human gene, the precise level of Dmel\mnb expression and function appears to be important. Animals homozygous for loss-of-function mutations of mnb exhibit an extended developmental time course, defects in olfactory and visual behavior, neuroanatomy defects, and neurophysiology defects. Pan-neuronal overexpression of mnb causes age-dependent degeneration of brain neurons, accelerated age-dependent decline in motor performance, shortened lifespan, modified presynaptic structures and enhanced spontaneous transmitter release, and slowed recovery from short-term depression of synaptic transmission. Physical and genetic interactions have been described for Dmel\mnb; see below and in the mnb gene report.
[updated Apr. 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 7; MRD7](https://omim.org/entry/614104)
[DUAL-SPECIFICITY TYROSINE PHOSPHORYLATION-REGULATED KINASE 1A; DYRK1A](https://omim.org/entry/600855)
A syndromic form of severe intellectual disability that may include microcephaly, facial dysmorphic features, seizures, and other neurodevelopmental anomalies. [from MIM:614104; 2020.07.20]
DYRK1A-related intellectual disability syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. [Gene Reviews, DYRK1A-related Intellectual Disability Syndrome; 2020.07.20]
Of 14 individuals assessed, all shared characteristics of congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features (Ji, et al., 2015; pubmed:25944381).
Of 14 individuals with de novo heterozygous variants of DYRK1A, five had microdeletions, three had small insertions or deletions (INDELs) and six had deleterious SNVs (Ji, et al., 2015; pubmed:25944381).
This disease is caused by heterozygous disruption of the DYRK1A gene. [from MIM:614104; 2020.07.20]
DYRK1A encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat; it catalyzes its autophosphorylation on serine/threonine and tyrosine residues. DYRK1A appears to play a significant role in a signaling pathway regulating cell proliferation and in brain development. [Gene Cards, DYRK1A; 2019.06.25]
Many to one: 2 human to 1 Drosophila; the second human gene is DYRK1B.
