Chromosome Rearrangements and Disease Group

	Chromosome rearrangements and disease group
	Disease-associated balanced chromosome rearrangements
	X-linked intellectual disability
	Team
	Publications

X-linked intellectual disability

During the last years we have identified a series of X-linked intellectual disability (XLID) genes through mapping translocation breakpoints and through mutation search in selected candidate genes located on proximal Xp11.

Truncation of SHROOM4/KIAA1202, ZNF41 and CDKL5/STK9 caused intellectual disability in female carriers, due to preferential inactivation of the normal X chromosome. We have shown that mutations in CDKL5/STK9 are responsible for the X-linked atypical Rett syndrome variant that is characterised by an early onset of seizures, with attacks starting in the first months of life.

Recently, we have discovered that truncation of the collybistin gene (ARHGEF9) on chromosome Xq caused a disturbed sleep-wake cycle, late-onset epileptic seizures, increased anxiety, aggressive behaviour and intellectual disability. In the patient defective collybistin transcripts are synthesized. These mRNAs no longer encode the pleckstrin homology (PH) domain of collybistin. Expression of truncated collybistin proteins in cultured neurons interferes with synaptic localization of endogenous gephyrin and GABA_A receptors. These results suggest that collybistin has a key role in membrane trafficking of gephyrin and selected GABA_A receptor subtypes involved in epilepsy, anxiety, aggression, insomnia and learning and memory.

Mutations in FTSJ1, JARID1C and PQBP1 result in non-syndromic and syndromic forms of XLID.

The polyglutamine binding protein 1 (PQBP1) gene plays an important role in XLID. Nine of the thirteen PQBP1 mutations known to date affect the AG hexamer in exon 4 and cause frameshifts introducing premature termination codons (PTCs). We investigated the impact of the mutations on PQBP1 mRNA and protein expression and found mutation-specific reduction of PQBP1 mRNAs carrying the PTCs that can be partially restored by blocking translation, thus indicating a role for the nonsense-mediated mRNA decay pathway. In addition, these mutations resulted in altered splicing of PQBP1 transcripts. Moreover, we found that a truncated PQBP1 protein is indeed present in the patients. Remarkably, patients with insertion/deletion mutations in the AG hexamer express significantly increased levels of a PQBP1 isoform.

Since two years we perform large-scale deep sequencing for finding the disease-causing mutation in families with XLID collected by the EURO-MRX consortium and associated groups.