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

Lissencephaly is a cortical malformation secondary to impaired neuronal mig ration resulting in mental retardation, epilepsy and motor impairment. It s hows a severity spectrum from agyria with a severely thickened cortex to po sterior band heterotopia only. The LIS1 gene on 17p13.3 encodes a 45 kDa pr otein named PAFAH1B1 containing seven WD40 repeats. This protein is require d for optimal neuronal migration by two proposed mechanisms: as a microtubu le-associated protein and as one subunit of the enzyme platelet-activating factor acetylhydrolase. Approximately 65% of patients with isolated lissenc ephaly sequence (ILS) show intragenic mutations or deletions of the LIS1 ge ne. We analyzed 29 non-deletion ILS patients carrying a mutation of LIS1 an d we report 15 novel mutations. Patients with missense mutations had a mild er lissencephaly grade compared with those with mutations leading to a shor tened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lisse ncephaly 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 put ative 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 severi ty seen in Miller-Dleker syndrome may be secondary to the loss of another c ortical development gene in the deletion of 17p13.3.