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Definition of the molecular genetic basis of band-like calcification with simplified gyration and polymicrogyria.
[Thesis]. Manchester, UK: The University of Manchester; 2013.
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Abstract
Identification of the genetic causes of developmental brain malformations has the potential to inform the processes of normal as well as abnormal brain development. We have described the clinical and radiological features in fifteen patients from nine families with a rare neurodevelopmental disorder, Band-like Calcification with simplified gyration and Polymicrogyria (BLC-PMG). The core phenotype comprises band-like intracranial calcification and polymicrogyria on brain imaging in patients with early onset epilepsy with microcephaly, minimal developmental progress and a raised CSF protein level. All patients studied were highly concordant for these features, particularly in relation to brain imaging. The inheritance was presumed to be autosomal recessive. Therefore, using autozygosity mapping, a region of homozygosity on chromosome 5q13 was identified common to six affected individuals from consanguineous families. Within the common interval OCLN was chosen as prime candidate due to the description of intracranial calcification in the knock-out mouse model. An OCLN pseudogene containing a copy of exons 5-9 with high sequence similarity provides extra complexity to OCLN sequencing analysis. Variants in the OCLN gene were identified by copy number analysis or sequencing in at least one affected individual from all nine families. Mutations were detected in the non-duplicated exons including intragenic deletions, an insertion and point mutations. Variants were also detected in the duplicated region of exons 5 and 6. Analysis of the variants detected was performed using in silico prediction software and laboratory based techniques including RT-PCR. Homozygous mutations in six families were predicted to affect the Marvel domain, a functional protein domain encoded by exon 3. The mechanism by which mutations in OCLN cause BLC-PMG is unknown. We postulate that occludin, and the Marvel domain in particular, is critical to effective protein function in the developing human brain and that mutations in OCLN cause BLC-PMG by disruption of the blood-brain barrier or downstream signalling events.