- Balanced translocations and abnormal phenotypes : what is the relationship ?
Periventricular nodular heterotopia (PNH) is a developmental brain malformation that is characterized by bilateral subependymal nodules of gray matter, resulting from the failure of clusters of neurons to migrate to the cortex. These gray matter nodules are easily visible on MRI along the walls of the lateral ventricles. Clinically, patients present with epilepsy and often with developmental handicaps in both children and adults. The clinical severity correlates with the size and the number of heterotopic nodules.
To date, two genes have been identified to cause PNH :
- the FLNA gene, in Xq28, causes X-linked dominant classical bilateral periventricular nodular heterotopia (BPNH) (Fox et al., 1998).
- the ARFGEF2 gene, in 20q13.1, causes autosomal recessive BPNH associated with microcephaly (Sheen et al., 2004).
Another locus is known on chromosome 5 but no gene is currently identified.
Mutations in the filamin A (or filamin 1) gene (FLNA/FLN1) are causing bilateral periventricular nodular heterotopia (BPNH) (Fox et al., 1998). By comparison to lissencephaly in which some observations show that the vast majority of neurones is able to migrate adequately (although the destination is incorrect), a number of neurons do not migrate in patients affected by this condition. Most mutations in FLNA are male lethal. This implies that the FLNA protein has an essential function during embryonic development. A number of boys with a mutation in the gene have been described (Guerrini et al., 2004) but all mutations are predicted to partially preserve the function of the protein (no null mutation has been identified in males). The FLNA gene encodes a large 280 kD protein which is essential for the formation of the actin cytoskeleton. It could be necessary for the polymerization/depolymerization cycles to proceed during the migratory processes. Although the FLNA protein is ubiquitously expressed, the patient’s phenotype is mostly neuronal and it does not involve 100% of cells. A compensation mechanism is thus predicted, possibly by another member of the filamin protein family : filamin B (FLNB). The two proteins are indeed highly homologous are they are able to form homo- and heterodimers (Sheen et al., 2002). In addition, these two proteins are co-expressed in the central nervous system.
It was shown that mutation in FLNA also cause four other X-linked conditions in males and females ( Robertson et al. 2003 , Robertson et al. 2006) : otopalatodigital syndromes types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. The phenotype of the patients is quite different from classical BPNH. All the mutations causing these diseases are conserving the open reading frame in the FLNA transcript in contrast to mutations causing BPNH.
Mutations in the ADP-ribosylation factor guanine nucleotide exchange factor 2 (ARFGEF2) gene in 20q13.1 are causing autosomal recessive periventricular nodular heterotopia. All the patients known to date have microcephaly. This type of malformation thus seems to involve not only migration but also proliferation of neuroblasts. The ARFGEF2 gene encodes a protein called BIG2 (brefeldin-A inhibited GEF2 protein or BIG2) which is implicated in the intracellular vesicular transport (Islam et al. 2007).