Journal Article

The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the <i>LIS1</i> gene

Carlos Cardoso, Richard J. Leventer, Naomichi Matsumoto, Julie A. Kuc, Melissa B. Ramocki, Stephanie K. Mewborn, Laura L. Dudlicek, Lorraine F. May, Patti L. Mills, Soma Das, Daniela T. Pilz, William B. Dobyns and David H. Ledbetter

in Human Molecular Genetics

Volume 9, issue 20, pages 3019-3028
Published in print December 2000 | ISSN: 0964-6906
Published online December 2000 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/9.20.3019
The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene

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Lissencephaly is a cortical malformation secondary to impaired neuronal migration resulting in mental retardation, epilepsy and motor impairment. It shows a severity spectrum from agyria with a severely thickened cortex to posterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa protein named PAFAH1B1 containing seven WD40 repeats. This protein is required for optimal neuronal migration by two proposed mechanisms: as a microtubule-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated lissencephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 gene. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 and we report 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P < 0.001). Our results suggest that the lissencephaly severity in ILS caused by LIS1 mutations may be predicted by the type and location of the mutation. Using a spectrum of ILS patients, we confirm the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function. We suggest that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes and hypothesize that the greater lissencephaly severity seen in Miller–Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3.

Journal Article.  7408 words.  Illustrated.

Subjects: Genetics and Genomics

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