This report describes rolandic epilepsy with paroxysmal exercise-induced dystonia (RE-EID), which shows autosomal recessive inheritance. The human gene implicated in this disease is TBC1D24. There is a single high-ranking ortholog of TBC1D24 in Drosophila, sky, for which RNAi targeting constructs, misexpression element constcuts, and other insertion alleles have been generated.
The human gene Hsap\TBC1D24 has been introduced into flies, both as wild-type and as mutant forms Hsap\TBC1D24 :p.Gly501Arg, Hsap\TBC1D24 :p.Arg360His, Hsap\TBC1D24ΔTLDc.UAS.GFP, and Hsap\TBC1D24 :p.Arg40Cys (which was previously associated with DOORS syndrome, see FBrf0233907), derived from patients with RE-EID.
Drosophila null mutants of sky expressing Hsap\TBC1D24 survive, indicating that it is capable of heterologous rescue (functional complementation), and Hsap\TBC1D24 protein is localized to presynaptic boutons of the neuromuscular junction, as is the case for sky. Both pathogenic mutant forms Hsap\TBC1D24 :p.Gly501Arg and Hsap\TBC1D24 :p.Arg360His localize to presynaptic boutons. All RE-EID patients in this study shared a mutation between residues 501 and 511 of Hsap\TBC1D24, in the TLDc domain. The Hsap\TBC1D24 :p.Gly501Arg mutant showed increased sensitivity to reactive oxygen species (ROS), as seen by defects in vesicle trafficking and large intracellular cisternae.
For other disease models associated with Hsap\TBC1D24, see 'TBC1D24-related disorders' (FBhh0000721).
[updated November 2019 by FlyBase; FBrf0222196]
[EPILEPSY, ROLANDIC, WITH PAROXYSMAL EXERCISE-INDUCED DYSTONIA AND WRITER'S CRAMP; EPRPDC](https://omim.org/entry/608105)
[TBC1 DOMAIN FAMILY, MEMBER 24; TBC1D24](https://omim.org/entry/613577)
Patients exhibited a syndrome with onset in infancy, featuring focal seizures, often hemifacial, centro-temporal EEG abnormalities, and paroxysmal dystonia precipitated by sustained exercise. They also exhibited forearm dystonia that caused writing to progressively become scribbling and then made it impossible after a few minutes. This manifestation is more akin to exercise-induced dystonia involving forearm muscles than to classical writer's cramp, in which dystonic posturing appears as soon as writing starts. (Guerrini et al. 1999, pubmed:10072049; Lüthy et al. 2019, FBrf0243006.)
All the RE-EID patients reported here harbour bi-allelic TBC1D24 mutations that can be described as hypomorphic TBC mutations (or mildly affecting the protein function, as in R360H) coupled to severe TLDc missense mutations clustering within 500 to 511 residues, which seems to be the hallmark for this condition. (Lüthy et al. 2019, FBrf0243006.)
The transmission pattern of EPRPDC in the family reported by Guerrini et al. 1999 (pubmed:10072049) was consistent with autosomal recessive inheritance. [from MIM:608105, 2019.11.06]
TBC1D24 encodes a protein containing a Tre2/Bub2/Cdc16 (TBC) domain, shared by Rab GTPase-activating proteins (Rab-GAPs). TBC domain-containing proteins regulate numerous vesicular membrane-trafficking and sorting processes by modulating the activity of Rab-GTPases. TBC1D24 interacts with the ADP ribosylation factor 6 (ARF6), a small GTP-binding protein involved in membrane exchange between plasma membrane and endocytic compartments. The protein also contains a TLDc domain, putatively involved in oxidative stress resistance. (Balestrini et al. 2016 and references therein, pubmed:27281533.)
One to one: 1 human gene to 1 Drosophila gene.
Single, high-scoring ortholog of human TBC1D24.
