This report describes paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy (PNKD3); PNKD3 exhibits autosomal dominant inheritance. The human gene implicated in this disease is KCNMA1, which encodes a large conductance, voltage and calcium-sensitive potassium channel (BK or MaxiK channel). KCNMA1 has been implicated in multiple neurological diseases (see MIM:600150). There is a single orthologous gene in Drosophila, slo, for which multiple genetic reagents have been generated, including loss-of-function mutations, overexpression and RNAi targeting constructs, and alleles caused by insertional mutagenesis. Dmel\slo is also orthologous to the related human gene KCNU1.
Multiple UAS constructs of the human Hsap\KCNMA1 gene have been introduced into flies, but have not been used in the context of this disease model.
A variant analogous to a known variant in PNKD3 was introduced into Dmel\slo by homologous recombination; the variant affects an exon shared by all isoforms of slo. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): E366G/E383G in the fly slo (corresponds to D434G in the human KCNMA1 gene). Animals heterozygous for the slo E366G/E383G mutation exhibit locomotor abnormalities at the larval and adult stages; seizure-like phenotypes have not been observed. In previous work in mammalian systems the D434G variant has been shown to act as a gain-of-function mutation by increasing BK channel Ca2+ sensitivity. Work in flies has allowed more detailed characterization of resulting defects in neurophysiology and the neuronal subtypes affected.
Several other diseases postulated to be associated with KCNMA1 have been studied in flies: see 'cardiac arrhythmia (postulated), KCNMA1-related' (FBhh0001351) and 'alcohol, response to, KCNMA1-related' (FBhh0000683). See also human disease model reports for dystonia (FBhh0000039) and epilepsy (FBhh0000268).
[updated May 2021 by FlyBase; FBrf0222196]
[PAROXYSMAL NONKINESIGENIC DYSKINESIA, 3, WITH OR WITHOUT GENERALIZED EPILEPSY; PNKD3](https://omim.org/entry/609446)
[POTASSIUM CHANNEL, CALCIUM-ACTIVATED, LARGE CONDUCTANCE, SUBFAMILY M, ALPHA MEMBER 1; KCNMA1](https://omim.org/entry/600150)
Familial paroxysmal nonkinesigenic dyskinesia is a disorder of the nervous system that causes episodes of involuntary movement. Paroxysmal indicates that the abnormal movements come and go over time. Nonkinesigenic means that episodes are not triggered by sudden movement. Dyskinesia broadly refers to involuntary movement of the body. [MedlinePlus (condition), Familial paroxysmal nonkinesigenic dyskinesia; 2021.05.23]
People with familial paroxysmal nonkinesigenic dyskinesia experience episodes of abnormal movement that are brought on by alcohol, caffeine, stress, fatigue, menses, or excitement or develop without a known cause. Episodes are not induced by exercise or sudden movement and do not occur during sleep. An episode is characterized by irregular, jerking or shaking movements that range from mild to severe. [MedlinePlus (condition), Familial paroxysmal nonkinesigenic dyskinesia; 2021.05.23]
The coexistence of epilepsy and paroxysmal dyskinesia in the same individual or family has been described in multiple studies. Du et al. (2005, pubmed:15937479) studied a large family of European descent with the combination of generalized epilepsy and paroxysmal dyskinesia (GEPD). Among 16 affected individuals, 4 developed isolated epileptic seizures, 7 had isolated paroxysmal nonkinesigenic dyskinesia, and 5 had both phenotypes. All patients except 1 had onset of symptoms in infancy or early childhood. [from MIM:609446; 2021.05.23]
Paroxysmal nonkinesigenic dyskinesia-3 with or without generalized epilepsy (PNKD3) is caused by heterozygous mutation in the KCNMA1 gene. [from MIM:609446; 2021.05.23]
MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can be formed by 2 subunits: the pore-forming alpha subunit, which is the product of the KCNMA1 gene, and the modulatory beta subunit. Intracellular calcium regulates the physical association between the alpha and beta subunits. [Gene Cards, KCNMA1; 2021.05.16]
The large-conductance voltage- and Ca(2+)-activated K+ channel, also called the BK channel, differs from other K+ channels in that it can be activated by both intracellular Ca(2+) ions and by membrane depolarization. The BK channel consists of 4 alpha subunits and 4 optional auxiliary beta subunits. The pore-forming alpha subunit is encoded by the KCNMA1 gene, which produces multiple isoforms through alternative splicing. The 4 beta subunits are encoded by different genes that show tissue-specific expression (Sausbier et al., 2004; pubmed:15194823). [from MIM:600150; 2021.05.23]
Many to one: 2 human to 1 Drosophila; the second human gene is KCNU1.
High-scoring ortholog of human KCNMA1; moderate-scoring ortholog of KCNU1 (1 Drosophila to 2 human). Dmel\slo shares 52% identity and 64% similarity with KCNMA1.
