Candidate genes in the homozygous region identified in CAMOS with identification of mutations in ZNF592. (a) Chromosomal region at 15q24–q26 containing the CAMOS candidate locus as previously identified,¹⁰ covering a 5.7-Mb (3.6-cM) region located between STR markers D15S206 (AFM299yf9) and D15S199 (AFM107 × g7). The 24 known genes lying in this region are schematically represented, with candidate genes tested in our study indicated in blue. ZNF592 is represented in red. ZNF592 is located at chromosome 15q25.3, covering a genomic region of ∼20 kb, and is transcribed in the direction centromere to telomere, as indicated by the black arrow. In the transcript of ZNF592, coding exons are represented in red and pink. ZNF592 is composed of 8 exons and the transcript is 4312-bp long (Acc. number BC094688), with a coding sequence of 3804 bp (exons 1–8). In the protein ZNF592, the 13 C2H2 zinc-finger (ZnF) domains are represented by boxes. Location of the mutation identified in this study is indicated by an asterisk in exon 6 of the gene, or in the eleventh ZnF of the protein. (b) Chromatograms showing the c.3136G>A mutation identified in ZNF592 exon 6 in Lebanese patients. Lebanese control sequence is shown in a control. (c) Effect of the mutation on the transcription: agarose gel migration showing a transcript of normal size in the patients. Chromatograms showing the absence of small deletions/insertions and the c.3136G>A missense mutation giving rise to the replacement of a glycine by an arginine in the protein (p.Gly1046Arg).

Three-dimensional structures of wild-type and mutant ZNF592 C2H2 zinc finger (ZnF). Wild-type (a) and mutant (b) eleventh C2H2 ZnF modeling using the freely available Swiss-Pdb Viewer software. In the mutant C2H2 ZnF domain 3D structure (panel b), the mutation of Gly41 to Arg41 results in the formation of a new hydrogen bond interaction between Arg41 and the adjacent tyrosine Tyr42.

Pedigree of the Lebanese family. Blackened symbols indicate the affected individuals. Gray circles indicate patients affected with diastrophic dysplasia, which is another autosomal recessive disease segregating in this pedigree.

Schematic representation of the zinc fingers (ZnFs) and conservation between species. (a) Schematic representation of ZnFs 10 and 11, showing the location of the mutated glycine at residue 1046, at the base of the eleventh ZnF. (b) Multiple alignments between human ZNF592 protein and several orthologs. The glycine at residue 1046 mutated in our study is indicated in red and is highly conserved among eutherian mammals.