Intracellular levels of the LIS1 protein correlate with clinical and neuroradiological findings in patients with classical lissencephaly

Abstract

We report on the genotype–phenotype correlation in 7 patients with classical lissencephaly carrying a heterozygous subtle mutation in the LIS1 gene. Six patients showed a mutation predicted to encode for a truncated protein, and one mutation altered a splicing site, resulting in skipping of exon 4. Western blot analysis performed on the lymphoblastoid cell line of 2 patients bearing truncating mutations indicated that the mutated allele did not produce a detectable amount of the LIS1 protein; whereas the analysis performed on the fibroblasts from the patient with a splice‐site mutation was suggestive of partial protein synthesis from the mutated allele. Although clinical and magnetic resonance imaging findings of patients with truncating mutations did not differ from those observed in patients with a heterozygous deletion, the patient bearing the exon‐skipping mutation had less severe clinical and brain involvement. Our data suggest that truncating mutations in the LIS1 gene are relatively common among patients with classical lissencephaly not bearing a heterozygous deletion at 17p13.3, and strengthen the relevance of correct intracellular dosage of the LIS1 protein in the neuronal migration process. Ann Neurol 1999;45:154–161

LIS1—no more no less

“…8 Indeed, just as our analysis detects partial protein synthesis from the mutated allele, a similar partial protein was detected in this specific patient. 8 Therefore, in the case of this mutation, it appears that the cells contain more LIS1 protein, normal amounts of the wild type protein resulting from the normal allele and in addition the sLIS1 product from the mutated allele. Compared to classic lissencephaly, 5 the N-terminal deletion patient showed a less severe degree of cortical abnormality including no seizures.…”

“…5 The mutation we generated resembles that of a patient with an in-frame N-terminal deletion. 8 Indeed, just as our analysis detects partial protein synthesis from the mutated allele, a similar partial protein was detected in this specific patient. 8 Therefore, in the case of this mutation, it appears that the cells contain more LIS1 protein, normal amounts of the wild type protein resulting from the normal allele and in addition the sLIS1 product from the mutated allele.…”

“…4,5 Subsequently, point mutations were detected as well. [6][7][8] In addition, a patient with an in-frame N-terminal deletion was Correspondence: Dr O Reiner, Department of Molecular Genetics, The Weizmann Institute of Science, 76100 Rehovot, Israel. Email: Orly.ReinerȰweizmann.ac.il reported, 8 showing a less severe degree of cortical abnormality.…”

LIS1 Missense Mutations

“…Our previous analysis indicated that truncated or internally deleted LIS1 protein is unlikely to fold correctly (11). This finding was supported by a study done in cells derived from lissencephaly patients, where no protein was detected from mutated alleles that were expected to result in a truncated protein (12). The five patients with point mutations that lead to a single amino acid substitution in LIS1 exhibit a variable phenotypic manifestation.…”

Poliovirus Protein 3A Binds and Deregulates LIS1, Causing Block of Membrane Protein Trafficking and Deregulation of Cell Division

“…58 Neurons are the most sensitive cells to the loss of LIS1 protein activity and decrease in LIS1 amount. 59 On the other hand, NUDEL, LIS1-interacting regulator of various types of dynein activities, including membranous organelle trafficking, 18,60 is important for assembly and transport of neurofilaments; NUDEL deficiency leading to neurodegeneration. 61 The titration of LIS1 by protein 3A could be one of the possible reasons of poliovirus induced neuronal disorder.…”