A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome

Abstract

Truncating mutations of the gene SALL4 on chromosome 20q13.13-13.2 cause Okihiro and acro-renal-ocular syndromes. Pathogenic missense mutations within the SALL4 or SALL1 genes have not yet been reported, raising the question which phenotypic features would be associated with them. Here we describe the first missense mutation within the SALL4 gene. The mutation results in an exchange of a highly conserved zinc-coordinating Histidine crucial for zinc finger (ZF) structure within a C2H2 double ZF domain to an Arginine. Molecular modeling predicts that this exchange does not result in a loss of zinc ion binding but leads to an increased DNA-binding affinity of the domain. The index patient shows mild features of Okihiro syndrome, but in addition cranial midline defects (pituitary hypoplasia and single central incisor). This finding illustrates that the phenotypic and functional effects of SALL4 missense mutations are difficult to predict, and that other SALL4 missense mutations might lead to phenotypes not overlapping with Okihiro syndrome.

Sumoylation Is Important for Stability, Subcellular Localization, and Transcriptional Activity of SALL4, an Essential Stem Cell Transcription Factor

“…The zinc finger domains are essential for SALL4 function since deletions or non-sense mutations lead to developmental disorders (14, 30 -32). In fact, a mutation with histidine (His-888 in SALL4A corresponding to His-451 in SALL4B) changed into arginine within the double zinc finger domain is associated with Okihiro syndrome in human (33). Lys-401, a crucial residue for sumoylation, also lies in close proximity to the second phosphorylation site, suggesting a possible regulatory interaction between these residues.…”

Identification of the nuclear localization signal of SALL4B, a stem cell transcription factor

“…Mutations of SALL4 gene have been detected in patients with several developmental disorders, and these mutations either occur in the transactivation domain or cause premature translational termination. 12,41,42 To date, no mutations have been reported that reside in the nuclear localization domain. It is likely that this type of mutations may severely disrupt the function of SALL4, thus leading to embryonic lethality.…”

Regulation and function of Spalt proteins during animal development

“…Some OS patients also show severe growth retardation, also seen in patients affected by TBS that might indicate pituitary dysfunctions associated with SALL4 mutations (Kohlhase et al, 2005;Miertus et al, 2006). A plausible explanation for the features shared by OS and TBS is that SALL4 can interact with SALL1.…”