AbstractPolymicrogyria (PMG) is a malformation of cortical development. It is characterised by
numerous, small gyri, separated from each other by superficial, sulci. For a long time PMG
was believed to be due to environmental causes only. Recent studies of familial forms of
PMG have lead to the identification of several genes and loci involved in PMG. The major
gene is the GPR56 gene, an orphan G-protein coupled receptor. To date, 11 mutations in the
GPR56 gene have been reported and they all result in bilateral frontoparietal PMG.
Mutations in the SRPX2 gene have been described in two families with specific language
impairment, in which one male patient also had bilateral perisylvian PMG.
All patients in this study have been diagnosed with PMG based on imaging. Group A
consists of patients with a variety of different PMG subtypes. Depending on the subtype of
PMG, we analysed one of the genes or both. Group B includes patients who have a
phenotype similar to that of the patient with PMG and a mutation in the SRPX2 gene
described in the literature. These patients were analysed only for SRPX2.
DNA was extracted from whole blood samples of the patients. Each exon was amplified
using PCR. After cycle sequencing the samples were loaded on a sequencer (ABI 3130xl)
Until now 34 patients have been sequenced: 1 patient for GPR56, 19 patients for SRPX2
(10 of these patients belong to group B) and 14 patients for both genes. No mutations could
be detected in our patients. Several known polymorphisms have been observed. Four
nucleotide substitutions, which have not been described in the literature, were identified.
Two were situated in non-coding regions of the GPR56 gene and two in non-coding regions
of the SRPX2 gene. But there was no evidence that one of these substitutions might be the
cause of the PMG.
Mutations in GPR56 were absent in group A. This indicates that mutations in the GPR56
gene might only be responsible for a small subgroup of PMG patients with a highly specific
phenotype. In group A, there were no mutations found in the SRPX2 gene either. This
suggests that mutations in this gene might be responsible for only a minority of PMG
patients. But there were also no mutations in the SRPX2 gene present in group B. So the
role of the SRPX2 gene in the development of PMG remains uncertain.
There are multiple mechanisms that could explain the absence of mutations in GPR56 and
SRPX2 in the patient sample we studied. We expect that there are a number of genes which
play an important role in the development of the cortex. These genes may cause PMG when
mutated. So an unknown number of possible candidate genes which might be associated
with the development of PMG are not looked at in this study. PMG is probably very
heterogenic: mutations in different genes may cause this malformation. In addition this
could be a multi-factorial disorder. This means that certain genetic constitutions, for
instance a distinct combination of polymorphisms in different genes, could make a patient
more vulnerable for environmental insults.
|Date of Award||22 Jun 2007|
|Supervisor||Linda De Meirleir (Promotor)|