SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism.

T he SALL genes, similar to the Drosophila gene spalt, probably encode zinc-finger transcription factors. In humans, four such genes have been identified to date. Mutations at SALL1 on chromosome 16q12.1 have been associated with Townes-Brocks syndrome and related phenotypes, 3 and mutations at SALL4 have been shown to be causative in patients with Okihiro/Duane-radial ray syndrome (OMIM No 607323). 5 SALL2 and SALL3 have not yet been associated with human disease. We previously reported frameshift and nonsense mutations in SALL4 in five of eight families segregating the Okihiro syndrome phenotype. A further report identified two frameshift mutations and one nonsense mutation in three affected kindreds, including the family reported by Okihiro et al. In a recent study of patients with the clinical diagnosis of Holt-Oram syndrome (OMIM No 142900), one additional frameshift mutation was reported from a family which turned out to have Okihiro syndrome rather than Holt-Oram syndrome. Furthermore, we reported three novel and one already identified SALL4 mutations in patients originally diagnosed as either Holt-Oram syndrome (later revised as Okihiro syndrome on the basis of the observation of a Duane anomaly in at least one of the affected family members in each family), acro-renal-ocular syndrome (OMIM No 102490), and Holt-Oram syndrome versus thalidomide embryopathy. In contrast to the report of Al-Baradie et al, we found no SALL4 mutations in three of eight families with clear Okihiro syndrome, the diagnosis being based on the presence of radial ray malformations in combination with a Duane anomaly. This finding led to the assumption that either mutations of another yet unidentified locus were responsible for the phenotype in those families, or that mutations within the SALL4 gene were present but outside the region analysed (that is, they were promotor or intronic mutations). SALL1 mutations causing Townes-Brocks syndrome and SALL4 mutations in Okihiro and related syndromes show quite different distributions. Compared with the mutational spectrum of SALL1 mutations, most of which reside in exon 2, 59 of the region encoding the first double zinc-finger domain, the SALL4 mutations detected so far seem to be evenly distributed over the gene. 5 9 10 It has not yet been possible to correlate the severity of the phenotype with the position of a SALL4 mutation. It has been speculated that the different phenotypic severity in two families with the same mutation c.2593CRT is a result of epigenetic factors. The nature of all known SALL4 mutations, all of which are truncating, suggested haploinsufficiency as the pathogenic mechanism. This is consistent with the observation that interstitial deletions of chromosome 20q, probably encompassing the SALL4 locus, are associated with phenotypes similar to Okihiro syndrome. 12 Based on the fact that the SALL1 knock-out mouse shows only kidney defects but no TBS-like phenotype, doubts were raised with respect to the hypothesis of SALL1 haploinsufficiency causing TBS. As an alternative explanation it was assumed that truncating SALL1 mutations could lead to the TBS phenotype by a dominant negative action, with truncated proteins interfering with nuclear transport of the wild type proteins. This would most probably result from dimerisation of wild type and mutant proteins mediated by the evolutionarily highly conserved glutamine-rich domain within the aminoterminal part of all known SAL-like proteins. 6 7 15–22 McLeskey Kiefer et al created a transgenic mouse harbouring a ‘‘typical’’ TBS mutation within the Sall1 gene in order to Key points