Jørgensen, Louise H6; Mosbech, Mai-Britt4; Færgeman, Nils J7; Graakjaer, Jesper8; Jacobsen, Søren V5; Schrøder, Henrik Daa6
1 Pathology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 Department of Biochemistry and Molecular Biology, Faculty of Science, SDU3 Department of Genetics, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU4 University of Southern Denmark, Institute of Biochemistry and Molecular Biology, Campusvej 55, 5230 Odense M, Denmark.5 Esbjerg Hospital6 Pathology, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU7 Department of Biochemistry and Molecular Biology, Faculty of Science, SDU8 Department of Genetics, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU
Spectrins and plakins are important communicators linking cytoskeletal components to each other and to cellular junctions. Microtubule-actin cross-linking factor 1 (MACF1) belongs to the spectraplakin family and is involved in control of microtubule dynamics. Complete knock out of MACF1 in mice is associated with developmental retardation and embryonic lethality. Here we present a family with a novel neuromuscular condition. Genetic analyses show a heterozygous duplication resulting in reduced MACF1 gene product. The functional consequence is affected motility observed as periodic hypotonia, lax muscles and diminished motor skills, with heterogeneous presentation among the affected family members. To corroborate these findings we used RNA interference to knock down the VAB-10 locus containing the MACF1 homologue in C. elegans, and we could show that this also causes movement disturbances. These findings suggest that changes in the MACF1 gene is implicated in this neuromuscular condition, which is an important observation since MACF1 has not previously been associated with any human disease and thus presents a key to understanding the essential nature of this gene.