A novel DCX missense mutation in a family with X-linked lissencephaly and subcortical band heterotopia syndrome inherited from a low-level somatic mosaic mother: Genetic and functional studies.
OBJECTIVE
To study the genetics and functional alteration of a family with X-linked lissencephaly and subcortical band heterotopia.


METHODS
Five affected patients (one male with lissencephaly, four female with subcortical band heterotopia) and their relatives were studied. Sanger sequencing of DCX gene, allele specific PCR and molecular inversion probe technique were performed. Mutant and wild type of the gene products, namely doublecortin, were expressed in cells followed by immunostaining to explore the localization of doublecortin and microtubules in cells. In vitro microtubule-binding protein spin-down assay was performed to quantify the binding ability of doublecortin to microtubules.


RESULTS
We identified a novel DCX mutation c.785A > G, p.Asp262Gly that segregated with the affected members of the family. Allele specific PCR and molecular inversion probe technique demonstrated that the asymptomatic female carrier had an 8% mutant allele fraction in DNA derived from peripheral leukocytes. This mother had 7 children, 4 of whom were affected and all four affected siblings carried the mutation. Functional study showed that the mutant doublecortin protein had a significant reduction of its ability to bind microtubules.


CONCLUSIONS
Low level mosaicism could be a cause of inherited risk from asymptomatic parents for DCX related lissencephaly-subcortical band heterotopia spectrum. This is particularly important in terms of genetic counselling for recurrent risk of future pregnancies. The reduced binding affinity of mutant doublecortin may contribute to developmental malformation of the cerebral cortex.
Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Department of Nursing, Meiho University, Taiwan.
Meng-Han
MH
Tsai
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
Pei-Wen
PW
Kuo
Department of Paediatrics, University of Washington, Seattle, USA.
Candace T
CT
Myers
Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Shih-Wen
SW
Li
Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Wei-Che
WC
Lin
Department of Pathology and Laboratory Medicine, Kaohsiung Veteran General Hospital, Kaohsiung, Taiwan.
Ting-Ying
TY
Fu
Department of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
Hsin-Yun
HY
Chang
Department of Paediatrics, University of Washington, Seattle, USA.
Heather C
HC
Mefford
Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Center for Translational Research in Biomedical Sciences, Kaohsiung, Taiwan; Department of Neurology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: ycchuang@cgmh.org.tw.
Yao-Chung
YC
Chang
Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan. Electronic address: tsaijw@ym.edu.tw.
Jin-Wu
JW
Tsai
D000328:Adult; D002648:Child; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics*; D004247:DNA / Q000235:genetics; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009030:Mosaicism; D020125:Mutation, Missense; D009479:Neuropeptides / Q000235:genetics*; D010290:Parents; D010375:Pedigree; D016133:Polymerase Chain Reaction
C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D004247:DNA
DCX; Double cortex; Doublecortin; Functional study; Lissencephaly; Microtubule; Somatic mosaicism; Subcortical band heterotopia