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

Abstract

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.

Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia

“…3 Exon 5 also contains the coiled-coil domain (amino acids 44 -78), which may play a role in PAFAH1B1 protein -protein interaction. 10 The disruption of these important functional domains of the LIS1 gene most likely explains the resulting lissencephaly phenotype observed. These two deletions may represent slightly milder mutations that manifest as grade 4 lissencephaly, as they do not result in a frame shift causing a prematurely truncated PAFAH1B1 protein.…”

“…We used the same grading system as in our earlier studies, which consists of completely absent gyri or agyria (grade 1), diffuse agyria with a few shallow sulci usually frontally (grade 2), mixed agyria and abnormally broad gyri or pachygyria (grade 3), diffuse pachygyria (grade 4), mixed pachygyria and SBH (grade 5) and SBH only (grade 6). 1,3,9,10 We searched our large brain malformation database for all patients with ILS or SBH for whom original brain imaging studies were available and reviewed by one of the authors (WBD). All patients were classified with attention to the pattern (severity and gradient), and the presence or absence of associated features.…”

“…1,3,9 Abnormalities of the LIS1 and DCX genes account for approximately 75% of ILS. 2,3,10 LIS1 abnormalities comprise whole gene deletions that are detectable by fluorescence in situ hybridization (FISH) analysis and mutations within the gene that are detectable by DNA sequencing. DCX abnormalities that result in ILS consist primarily of mutations within the gene.…”

“…2,3,11 -13 For both the LIS1 and DCX genes, mutations that abolish function such as entire gene deletions, nonsense, frameshift and splicing mutations generally result in a more severe phenotype, while missense mutations tend to result in the milder phenotypes. 9,10,13,14 Intragenic deletions of the LIS1 and DCX genes also result in lissencephaly, but the frequency of these types of mutation as well as the associated disease severity has not been well characterized. Intragenic deletion mutations of the LIS1 gene, detected by Southern blot, have previously been found to account for approximately 8% of diseasecausing mutations.…”

“…Intragenic deletion mutations of the LIS1 gene, detected by Southern blot, have previously been found to account for approximately 8% of diseasecausing mutations. 2,10 We set out to determine the incidence of intragenic deletions and duplications in the LIS1 and DCX genes in patients with varying degrees of lissencephaly and SBH.…”