title: Duplication in the microtubule-actin cross-linking factor 1 gene causes a novel neuromuscular condition.
abstract: 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.
authors.affiliation: University of Southern Denmark and Odense University Hospital, Institute of Clinical Research, Pathology, SDU muscle research cluster, J.B. Winsløws Vej 15, 2., 5000 Odense C, Denmark.
authors.forename: Louise H
authors.initials: LH
authors.lastname: Jørgensen
authors.affiliation: University of Southern Denmark, Institute of Biochemistry and Molecular Biology, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Mai-Britt
authors.initials: MB
authors.lastname: Mosbech
authors.affiliation: University of Southern Denmark, Institute of Biochemistry and Molecular Biology, Campusvej 55, 5230 Odense M, Denmark.
authors.forename: Nils J
authors.initials: NJ
authors.lastname: Færgeman
authors.affiliation: Vejle Hospital, Clinical Genetics Department, Vejle, DK.
authors.forename: Jesper
authors.initials: J
authors.lastname: Graakjaer
authors.affiliation: Esbjerg Hospital, Paediatrics, Esbjerg, DK.
authors.forename: Søren V
authors.initials: SV
authors.lastname: Jacobsen
authors.affiliation: University of Southern Denmark and Odense University Hospital, Institute of Clinical Research, Pathology, SDU muscle research cluster, J.B. Winsløws Vej 15, 2., 5000 Odense C, Denmark.
authors.forename: Henrik D
authors.initials: HD
authors.lastname: Schrøder
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D055028:Comparative Genomic Hybridization; D005260:Female; D020440:Gene Duplication; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C095003:MACF1 protein, human; D008840:Microfilament Proteins; D012333:RNA, Messenger