Subcortical Band Heterotopia in Rare Affected Males Can be Caused by Missense Mutations in DCX (XLIS) or LIS1

• Published in: Human molecular genetics Vol. 8; no. 9; pp. 1757 - 1760
• Main Authors: Pilz, Daniela T., Kuc, Julie, Matsumoto, Naomichi, Bodurtha, Joann, Bernadi, Bruno, Tassinari, Carlo A., Dobyns, William B., Ledbetter, David H.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.09.1999
• Subjects: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Biological and medical sciences; Brain - abnormalities; Classical genetics, quantitative genetics, hybrids; DNA Mutational Analysis; Exons - genetics; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Human; Humans; Magnetic Resonance Imaging; Male; Malformations of the nervous system; Medical sciences; Microtubule-Associated Proteins - genetics; Mutation, Missense; Neurology; Neuropeptides - genetics; Human; Sex linked character; Nervous system diseases; Phenotype; Missense mutation; Malformation; Lissencephaly; Central nervous system disease; Genotype; Genetics; Cerebral disorder
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/8.9.1757

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 XLS) 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 mutationinexon 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 LS1 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.