title: Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1.
abstract: Subcortical band heterotopia (SBH) are bilateral and symmetric ribbons of gray matter found in the central white matter between the cortex and the ventricular surface, which comprises the less severe end of the lissencephaly (agyria-pachygyria-band) spectrum of malformations. Mutations in DCX (also known as XLIS ) have previously been described in females with SBH. We have now identified mutations in either the DCX or LIS1 gene in three of 11 boys studied, demonstrating for the first time that mutations of either DCX or LIS1 can cause SBH or mixed pachygyria-SBH (PCH-SBH) in males. All three changes detected are missense mutations, predicted to be of germline origin. They include a missense mutation in exon 4 of DCX in a boy with PCH-SBH (R78H), a different missense mutation in exon 4 of DCX in a boy with mild SBH and in his mildly affected mother (R89G) and a missense mutation in exon 6 of LIS1 in a boy with SBH (S169P). The missense mutations probably account for the less severe brain malformations, although other patients with missense mutations in the same exons have had diffuse lissencephaly. Therefore, it appears likely that the effect of the specific amino acid change on the protein determines the severity of the phenotype, with some mutations enabling residual protein function and allowing normal migration in a larger proportion of neurons. However, we expect that somatic mosaic mutations of both LIS1 and DCX will also prove to be an important mechanism in causing SBH in males.
authors.affiliation: Institute for Medical Genetics, University Hospital of Wales, Cardiff CF4 4XW, UK.
authors.forename: D T
authors.initials: DT
authors.lastname: Pilz
authors.forename: J
authors.initials: J
authors.lastname: Kuc
authors.forename: N
authors.initials: N
authors.lastname: Matsumoto
authors.forename: J
authors.initials: J
authors.lastname: Bodurtha
authors.forename: B
authors.initials: B
authors.lastname: Bernadi
authors.forename: C A
authors.initials: CA
authors.lastname: Tassinari
authors.forename: W B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: D H
authors.initials: DH
authors.lastname: Ledbetter
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001921:Brain / Q000002:abnormalities*; D004252:DNA Mutational Analysis; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009479:Neuropeptides / Q000235:genetics*
chemical_list: C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human