Axonemal protofilament ribbons, DM10 domains, and the link to juvenile myoclonic epilepsy

Abstract

Juvenile myoclonic epilepsy (JME) is a common neurological disorder that results in short uncontrolled muscle contractions and sometimes more severe seizures. Genetic studies have suggested that JME may be caused by mutations in EFHC1. The Efhc1 protein consists of three DM10 domains and a C-terminal region containing a potential Ca 2þ -binding motif. In Chlamydomonas, a protein (Rib72) of almost identical domain structure is a component of the protofilament ribbons within the doublet microtubules of the flagellar axoneme. Here I discuss recent work that supports assignment of human Efhc1 as a ciliary component and the resulting implications for the mechanism of disease causation. Cell Motil.

EFHC1, a protein mutated in juvenile myoclonic epilepsy, associates with the mitotic spindle through its N-terminus

“…How the human mutations of EFHC1 interfere with its function at the mitotic apparatus and how they might contribute to epilepsy through its role in mitosis and/or cilia associated function [27] is currently being investigated in our laboratory. 5 -The N-terminus of EFHC1 mediates its association with the mitotic spindle.…”

The flagellum of Trypanosoma brucei: New tricks from an old dog

“…For many of these genes, the works by Baron et al and Broadhead et al represent, to our knowledge, the first time that the connection to human disease has been made and, in some cases, the first functional characterization. For example, while it was known that protofilament ribbon protein 72 (Rib72) was biochemically associated with flagellar protofilament ribbons (Patel-King, 2002;Ikeda and Kamiya, 2003), and that mutations in Rib72 are associated with juvenile myoclonic epilepsy (Suzuki et al, 2004;King, 2006), studies in T. brucei demonstrated a requirement for Rib72 in flagellar motility (Baron et al, 2007b). Similarly, mutations in hydin induce hydrocephalus and studies in T. brucei were among the first to show a specific flagellum function, demonstrating that hydin knockdown leads to defects in the positioning and formation/ stability of the axonemal central pair (Broadhead et al, 2006;Dawe et al, 2007;Lechtreck and Witman, 2007).…”

Evolution and persistence of the cilium

“…According to this hypothesis of ciliary origin, the original invading virus would deliver tektin and associated ribbon proteins, e.g. rib74 [Linck and Norrander, 2003;King, 2006]-as well as unique tubulin genes, to the forming eukaryotic cell, making possible the polymerization of the compound microtubules of the centriole, and later of the axoneme. Tektins are immunologically and structurally related to intermediate filament proteins [Chang and Piperno, 1987;Steffen and Linck, 1989].…”