This report describes intellectual disability, X-linked, CASK-related, which includes several syndromic forms of intellectual disability (MIM:300749, FBhh0000865; MIM:300422, FBhh0000866). The human gene implicated in this disease is CASK, which encodes a calcium/calmodulin-dependent serine protein kinase with roles in synaptic transmembrane protein anchoring and ion channel trafficking. There is a single orthologous gene in Drosophila, Dmel\CASK, for which hypomorphic alleles resulting from imprecise excision of an insertion, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\CASK gene have been introduced into flies. Heterologous rescue (functional complementation) has been observed assying the memory-defective phenotype of a hypomorphic CASK allele.
Animals homozygous for loss-of-function mutations of Dmel\CASK exhibit memory and learning defects, neurophysiology and neuroanatomy defects, and locomotor defects. Physical and genetic interactions have been described for Dmel\CASK (see below and in the gene report for CASK), including with the fly gene CaMKII. Several human orthologs of Dmel\CaMKII have also been implicated in intellectual disability; see the human disease model report, 'intellectual disability, autosomal dominant, CAMK2-related' (FBhh0000870). Work done in flies supports a role of CASK in the regulation of CaMKII autophosphorylation.
[updated Aug. 2018 by FlyBase; FBrf0222196]
CASK-related disorders include a spectrum of phenotypes in both females and males. MICPCH is typically seen in females with moderate to severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss; MICPCH is generally associated with pathogenic loss-of-function variants in CASK. In individuals and families with milder (i.e., hypomorphic) pathogenic variants, the clinical phenotype is usually that of X-linked intellectual disability (XLID) with or without nystagmus and additional clinical features. [Gene Reviews, CASK-Related Disorders; 2018.08.14]
MICPCH syndrome is caused by heterozygous mutation or deletion in the CASK gene, typically resulting in complete loss of function of one allelic copy of the gene; this syndrome is observed in females. FGS4 and mental retardation with or without nystagmus are typically associated with missense or hypomorphic mutations in the CASK gene and are usually observed in males. [from MIM:300749 and MIM:300422; 2018.08.14]
CASK encodes a calcium/calmodulin-dependent serine protein kinase, a MAGUK (membrane-associated guanylate kinase) protein family member; has roles in synaptic transmembrane protein anchoring and ion channel trafficking; located at synapses in the brain. [Gene Cards, CASK; 2018.08.14]
One to one: 1 human to 1 Drosophila
High-scoring ortholog of human CASK; Dmel\CASK shares 60% identity and 75% similarity with the human gene.
