An isolated case of lissencephaly caused by the insertion of a mitochondrial genome-derived DNA sequence into the 5' untranslated region of the PAFAH1B1 (LIS1) gene

Classical (type 1) lissencephaly is a neuronal migration disorder characterised by agyria (absent cerebral convolutions) and pachygyria (reduced, broad cerebral convolutions), a thickened cortex (grey matter), mental retardation and epileptic seizures. It can occur either as part of the contiguous deletion disorder, Miller-Dieker syndrome, or as an isolated condition termed isolated lissencephaly sequence (ILS) [1]. Most cases of ILS are caused by defects in either the PAFAH1B1 (LIS1) or the DCX genes. Patients with a PAFAH1B1 gene alteration have a more severe cerebral phenotype posteriorly, whereas those with a DCX gene defect have a more severe cerebral phenotype anteriorly. The heterozygous deletion of a further gene, YWHAE (located 1 megabase [Mb] from PAFAH1B1 on 17p13.3 and encoding the 14-3-3ε protein), together with PAFAH1B1 in patients with Miller-Dieker syndrome, is known to increase the severity, usually with generalised agyria [2].The PAFAH1B1 gene (MIM# 601545) was the first gene to be implicated in the pathogenesis of lis-sencephaly and encodes the non-catalytic α-subunit of the intracellular 1b isoform of platelet-activating factor acetylhydrolase [3]. It spans ~92 kilobases (kb) of genomic DNA and contains 11 exons, the first two of which contribute to the 5' untranslated region (5' UTR). Although the deletion of the entire PAFAH1B1 gene is the most common mutation encountered in lissencephaly patients, a considerable number of intragenic lesions have now been reported [4-8]. In general, however, it appears that neither the type nor the position of known intragenic mutations in the PAFAH1B1 gene are indicative of the likely clinical severity of the condition [9]. Here, we report a highly unusual lissencephaly-causing mutation in the PAFAH1B1 gene, which involves the insertion of mitochondrial genome-derived DNA sequence into the 5' UTR of the gene.Exons 2 to 11 of the human PAFAH1B1 gene were polymerase chain reaction (PCR) amplified (primer details