LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.
BACKGROUND
Classical lissencephaly is a disorder of neuroblast migration with most patients having mutations of either the LIS1 or DCX genes. Most patients with lissencephaly secondary to LIS1 mutations have a severe malformation consisting of generalized agyria and pachygyria. However, increasing experience suggests that the phenotypic spectrum is wider than previously thought.


METHODS
The authors describe the clinical and imaging features and mutation data of the five known patients with missense mutations of the LIS1 gene and emphasize one patient with normal intelligence.


RESULTS
Patients with a missense mutation of the LIS1 gene have a wider and milder spectrum of cortical malformations and clinical sequelae compared with patients with other mutation types.


CONCLUSIONS
Milder and more variable phenotypes seen in patients with missense mutations of LIS1 are likely a consequence of suboptimal function of the mutant LIS1 protein, rather than complete loss of function of this protein. The authors suggest that the few patients found thus far with missense mutations of LIS1 results from an underascertainment of patients with more subtle malformations and that abnormalities of the LIS1 gene may account for a greater spectrum of neurologic problems in childhood than has previously been appreciated.
Leventer
R J
RJ
Department of Human Genetics, The University of Chicago, IL 60637, USA.
Cardoso
C
C
Ledbetter
D H
DH
Dobyns
W B
WB
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001921:Brain / Q000002:abnormalities* / Q000473:pathology*; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007360:Intelligence / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype
D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human