title: Identification of a homozygous splice site mutation in the dynein axonemal light chain 4 gene on 22q13.1 in a large consanguineous family from Pakistan with congenital mirror movement disorder.
abstract: Mirror movements (MRMV) are involuntary movements on one side of the body that mirror voluntary movements on the opposite side. Congenital mirror movement disorder is a rare, typically autosomal-dominant disorder, although it has been suspected that some sporadic cases may be due to recessive inheritance. Using a linkage analysis and a candidate gene approach, two genes have been implicated in congenital MRMV disorder to date: DCC on 18q21.2 (MRMV1), which encodes a netrin receptor, and RAD51 on 15q15.1 (MRMV2), which is involved in the maintenance of genomic integrity. Here, we describe a large consanguineous Pakistani family with 11 cases of congenital MRMV disorder reported across five generations, with autosomal recessive inheritance likely. Sanger sequencing of DCC and RAD51 did not identify a mutation. We then employed microarray genotyping and autozygosity mapping to identify a shared region of homozygosity-by-descent among the affected individuals. We identified a large autozygous region of ~3.3 Mb on chromosome 22q13.1 (Chr22:36605976-39904648). We used Sanger sequencing to exclude several candidate genes within this region, including DMC1 and NPTXR. Whole exome sequencing was employed, and identified a splice site mutation in the dynein axonemal light chain 4 gene, DNAL4. This splice site change leads to skipping of exon 3, and omission of 28 amino acids from DNAL4 protein. Linkage analysis using Simwalk2 gives a maximum Lod score of 6.197 at this locus. Whether or how DNAL4 function may relate to the function of DCC or RAD51 is not known. Also, there is no suggestion of primary ciliary dyskinesis, situs inversus, or defective sperm in affected family members, which might be anticipated given a putative role for DNAL4 in axonemal-based dynein complexes. We suggest that DNAL4 plays a role in the cytoplasmic dynein complex for netrin-1-directed retrograde transport, and in commissural neurons of the corpus callosum in particular. This, in turn, could lead to faulty cross-brain wiring, resulting in MRMV.
authors.affiliation: Molecular Neuropsychiatry and Development (MiND) Lab, Centre For Addiction and Mental Health, Campbell Family Mental Health Research Institute, R32, 250 College Street, Toronto, ON, M5T 1R8, Canada.
authors.forename: Iltaf
authors.initials: I
authors.lastname: Ahmed
authors.forename: Kirti
authors.initials: K
authors.lastname: Mittal
authors.forename: Taimoor I
authors.initials: TI
authors.lastname: Sheikh
authors.forename: Nasim
authors.initials: N
authors.lastname: Vasli
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.forename: Anna
authors.initials: A
authors.lastname: Mikhailov
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Ohadi
authors.forename: Huda
authors.initials: H
authors.lastname: Mahmood
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.forename: Attya
authors.initials: A
authors.lastname: Bhatti
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.forename: Myriam
authors.initials: M
authors.lastname: Srour
authors.forename: Peter
authors.initials: P
authors.lastname: John
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D056444:Axonemal Dyneins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003241:Consanguinity; D056915:DNA Copy Number Variations; D008040:Genetic Linkage; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000151:congenital / Q000235:genetics*; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D012326:RNA Splicing; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D056444:Axonemal Dyneins; C000593273:DNAL4 protein, human
references.citation: Mov Disord. 2003 Nov;18(11):1294-300
references.pmid: 14639670
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W593-9
references.pmid: 19465395
references.citation: Science. 2010 Apr 30;328(5978):592
references.pmid: 20431009
references.citation: Brain. 2013 Nov;136(Pt 11):3333-46
references.pmid: 24056534
references.citation: Mov Disord. 2010 Jul 30;25(10):1317-34
references.pmid: 20564735
references.citation: Neurology. 2009 Sep 1;73(9):729-31
references.pmid: 19720981
references.citation: Mol Biol Cell. 2008 Sep;19(9):3724-34
references.pmid: 18579685
references.citation: PLoS Biol. 2006 Apr;4(4):e86
references.pmid: 16602821
references.citation: Hum Hered. 2001;52(3):121-31
references.pmid: 11588394
references.citation: Genome Biol. 2010;11(10):R99
references.pmid: 20932289
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: J Biochem Biophys Methods. 1992 Dec;25(4):193-205
references.pmid: 1494032
references.citation: Am J Hum Genet. 1999 Dec;65(6):1508-19
references.pmid: 10577904
references.citation: Neural Plast. 2012;2012:627816
references.pmid: 23304559
references.citation: Am J Hum Genet. 2011 Apr 8;88(4):440-9
references.pmid: 21457909
references.citation: Am J Hum Genet. 1996 Jun;58(6):1323-37
references.pmid: 8651310
references.citation: Nature. 2008 Dec 4;456(7222):611-6
references.pmid: 19052621
references.citation: Dev Med Child Neurol. 1993 Aug;35(8):699-707
references.pmid: 8335159
references.citation: Nucleic Acids Res. 2010 Sep;38(16):e164
references.pmid: 20601685
references.citation: Am J Hum Genet. 2012 Feb 10;90(2):301-7
references.pmid: 22305526
references.citation: Dev Biol. 2010 Nov 1;347(1):53-61
references.pmid: 20707998
references.citation: Brain. 1991 Feb;114 ( Pt 1B):381-403
references.pmid: 2004248
references.citation: J Cell Sci. 2013 Jul 15;126(Pt 14):3070-81
references.pmid: 23641072
references.citation: Bioinformatics. 2011 Apr 1;27(7):1011-2
references.pmid: 21278192
references.citation: Blood. 2005 Jan 15;105(2):784-93
references.pmid: 15454493
references.citation: J Neurol. 2011 Nov;258(11):1911-9
references.pmid: 21633904
references.citation: Am J Hum Genet. 2002 Feb;70(2):496-508
references.pmid: 11791215
references.citation: Development. 1996 Oct;122(10):2955-63
references.pmid: 8898210
references.citation: Cell. 2010 May 14;141(4):632-44
references.pmid: 20434207
references.citation: Arch Neurol. 1967 Jun;16(6):620-3
references.pmid: 6026070
references.citation: Nature. 2005 Oct 20;437(7062):1173-8
references.pmid: 16189514
references.citation: Neurology. 2011 Jan 18;76(3):260-4
references.pmid: 21242494