- Balanced translocations and abnormal phenotypes : what is the relationship ?
A mutation in the OPHN1 gene, encoding Oligophrenin, has been reported for the first time in a family of non-specific XLMR. Since then , we and others demonstrated that mutations in OHPN1 were associated with syndromic mental retardation with cerebellar hypoplasia (Philip et al, 2003 ; Bergmann et al, 2003). These findings were confirmed by the reappraisal of the first family, demonstrating similar MRI findings. We made a review of the literature in order to propose a better definition of the clinical phenotype. Neuroradiological findings were identical in all male patients: cerebellar hypoplasia predominating on the lower vermis, cortical atrophy and variable ventricular dilatation requiring ventriculo-peritoneal shunting in two cases. Mental retardation was constant, usually moderate (IQ around 50), predominating on language. There was no associated ataxia, except in one family. Strabismus was present in three families. In addition, we demonstrated that all male patients exhibit a characteristic facial appearance. Heterozygous females exhibit mild mental retardation and slight facial dysmorphism. All five mutations are non-sense mutations or small frameshift deletions. No reccurent mutation or hot-spot was observed, demonstrating that a complete mutation screening of the gene is mandatory in suspected cases (Chabrol et al., 2005).
In collaboration with colleagues from the center of human genetics of Gerpine in Belgium (Dr Lionel van Maldergem), we studied a family in which a pericentric inversion of the X chromosome is segregating. The affected males are carrier of the inversion and are affected by severe mental retardation. We have shown that this chromosomal rearrangement is disrupting a new gene called KIAA2022. The corresponding transcript is no longer detectable in the patient's cells. This gene is very strongly expressed in the fetal brain (Cantagrel et al., 2004). We now have begun the characterization of this new human gene and we are studying its expression pattern during the development and the intracellular localization of the corresponding protein.
In collaboration with our colleagues from Lebanon (André Megarbané's group), we are characterizing a balanced de novo translocation in a girl with moderate MR and dysmorphic features. We are currently cloning the translocation breakpoints and we hope to identify a candidate gene for this phenotype.
We have characterized a de novo balanced translocation identified in a patient with severe MR and severe central hypotonia. The patient does not have epilepsy. Nerve conduction velocity and electromyogram are normal. EEG and MRI are also normal. The molecular characterization of the chromosomal rearrangement shows that a gene is interrupted on chromosome 13. This gene encodes a protein of unknown function. Preliminary analysis reveals that it is only expressed in brain and testis, making it a good candidate for the neurological phenotype of our patient. Additional studies are ongoing.
We have characterized a de novo balanced translocation identified in a patient with moderate MR and bilateral deafness. The molecular characterization of the translocation reveals that a gene is disrupted on chromosome 15. This gene encodes a protein of unknown function. Preliminary studies show that this gene is highly expressed in the fetal brain, making it a good candidate for the phenotype of the patient. Additional studies are ongoing.