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A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
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Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with

P A Leegwater1, B Q Yuan, J van der Steen

  • 1Department of Clinical Chemistry, Free University Medical Center, 1007 MB Amsterdam, The Netherlands. leegwater@azvu.nl

American Journal of Human Genetics
|March 20, 2001
PubMed

Insights

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is caused by mutations in the MLC1 gene. This genetic discovery offers new insights into the molecular basis of this rare neurological disorder.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare autosomal recessive neurological disorder.
  • Characterized by macrocephaly, motor function decline, ataxia, spasticity, and mental deterioration.
  • Brain MRI shows swelling, diffuse white-matter abnormalities, and subcortical cysts.

Purpose of the Study:

  • To identify the genetic cause of Megalencephalic leukoencephalopathy with subcortical cysts (MLC).
  • To narrow down the critical genetic region for MLC on chromosome 22q(tel).
  • To investigate potential genetic heterogeneity in MLC.

Main Methods:

  • Linkage analysis of 11 informative families with MLC.
  • Microsatellite marker analysis on chromosome 22q(tel).
  • Mutation screening of candidate genes, including KIAA0027 (renamed MLC1).

Main Results:

  • A critical region of approximately 250 kb was identified on chromosome 22q(tel).
  • Mutations in the MLC1 gene were found in seven informative and six uninformative families.
  • Twelve different mutations, including stop codons, frameshifts, and splice mutations, were identified in MLC1.
  • One family showed no linkage to chromosome 22q(tel), suggesting genetic heterogeneity.

Conclusions:

  • Mutations in the MLC1 gene are a primary cause of Megalencephalic leukoencephalopathy with subcortical cysts (MLC).
  • The MLC1 gene encodes a putative membrane protein.
  • Genetic heterogeneity likely contributes to MLC in some families.

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