Subject(s)
Abnormalities, Multiple/genetics , Anal Canal/abnormalities , Arginine/genetics , Ear/abnormalities , Kidney/abnormalities , Limb Deformities, Congenital/genetics , Mutation, Missense/genetics , Transcription Factors/genetics , Abnormalities, Multiple/epidemiology , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Incidence , Infant, Newborn , Limb Deformities, Congenital/epidemiology , Male , Nuclear FamilyABSTRACT
We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of "thalidomide embryopathy" might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 20/genetics , Duane Retraction Syndrome/genetics , Transcription Factors/genetics , Abnormalities, Multiple/pathology , Base Sequence , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Duane Retraction Syndrome/pathology , Family Health , Female , Fetal Diseases/chemically induced , Fetal Diseases/genetics , Hand Deformities, Congenital/pathology , Heart Septal Defects, Atrial/pathology , Humans , Kidney/abnormalities , Male , Mutation , Pedigree , Phenotype , Thalidomide/adverse effects , Thumb/abnormalitiesABSTRACT
SALL4 is one out of four human homologues of the DROSOPHILA region-specific homeotic gene SPALT(SAL). Heterozygous mutations of SALL4 on chromosome 20q13.13--> q13.2 cause the autosomal dominant Okihiro syndrome which is characterized by radial limb defects, Duane anomaly and hearing loss. We have partially cloned the murine homologue of this gene, named SALL4, and completed the coding sequence by comparison to available EST and genomic sequences in the GenBank database. This comparison also revealed the chromosomal location of SALL4 on mouse chromosome 2H3 and suggested that a predicted testis expressed gene TEX20 at the very same locus is most likely not a gene on its own but part of the SALL4 3' UTR. We analyzed the expression of SALL4 during early embryogenesis by whole mount in situ hybridization and in the adult mouse by Northern blotting. In adult tissues, SALL4 expression is only found in testis and ovary. During embryonic development, SALL4 expression is widespread in early embryos and becomes gradually confined to the head region and the primitive streak. Prominent expression in the developing midbrain, branchial arches and the limbs suggests an important function of SALL4 during development of these structures as expected from the observation in Okihiro syndrome patients.
