Mental Retardation Associated With Retinitis Pigmentosa in the Xp11.3 Deletion Syndrome: ZNF674 in the Dock. Guilty or Innocent?

Abstract

Purpose: : X-linked retinitis pigmentosa (XLRP) is among the most severe retinal dystrophies affecting children and causing severe visual dysfunction before the age of 30. Two genes account for almost all XLRP cases: RPGR (Xp21.1-11.4) and RP2 (Xp11.23) which account for ca. 70% and 30% of cases, respectively. In the 90s, a 1.2 Mb deletion in the Xp11.3 region was reported in two independent families segregating XLRP with mental retardation (MR). While the retinal dystrophy was ascribed to the deletion of the RP2 gene, the mental retardation was suggested to be accounted for by the loss of the ZNF674 gene which mutations were independently reported to account for isolated XLMR. Here, we report two unrelated families with XLRP with no mental retardation harbouring a large Xp11.23 deletion. The purpose of this study was to characterize the deletion boundaries and to determine whether the absence of mental retardation could be accounted for by the absence of ZNF674 deletion.

Methods: : Two large unrelated families were ascertained gathering respectively 7 and 2 males affected with severe forms of XLRP. Indirect studies with highly polymorphic markers of the RP3 and RP2 loci were undertaken to direct the molecular study towards one gene or the other. The Xp11.23 deletion identified in both families was characterized by PCR using STS markers of the region.Results and

Conclusions: : Indirect studies at the RP3 and RP2 loci in both families suggested the existence of a large deletion encompassing RP2 and polymorphic markers flanking the 5 'region of the gene. PCR-based studies of STS markers in the Xp11.23 region demonstrated that in one of the family the deletion included PHF16 (first two exons) RP2, SLC9A7, CHST7, and ZNF674 while in the second the deletion encompassed the first three exons of RP2, SLC9A7, CHST7, and ZNF674. The breakpoints of both deletions are under characterization. Owing to the loss of ZNF674, affected males patients were interviewed and examined to state on their mental development. None of them presented with any mental disabilities raising the question to know whether the loss of ZNF674 accounted for the mental retardation in families co-segreating the feature with XLRP.

Keywords: retina • retinal degenerations: hereditary • positional cloning