Disease relevance of SALL1

• Exclusion of the SALL1 gene as a cause of branchio-oculo-facial syndrome [1].
• Arising from our observation of several malformations in Okihiro syndrome patients which are also described in Townes-Brocks syndrome, we postulated that Okihiro syndrome might result from mutation of another member of the human SALL gene family [2].
• The Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome presenting as an association of imperforate anus, triphalangeal and supernumerary thumbs, malformed ears and sensorineural hearing loss [3].
• Although SNV is an avian retrovirus, the nucleotide sequences in the R, U5, TBS, and PU region are more similar to the mammalian type C than to the avian type C retroviruses [4].
• Mutations in the human homologue of csal1, termed Hsal1/SALL1, result in a condition known as Townes-Brocks syndrome (TBS), which is characterized by preaxial polydactyly [5].

High impact information on SALL1

• TBS therefore represents another human developmental disorder caused by mutations in a putative C2H2 zinc-finger transcription factor [6].
• Carbon dioxide partial pressure increased from a mean of 27.3 mmHg in common duct bile to greater than 100 mmHg in gallbladder bile at [TBS] = 180 mM, then declined to approximately 36 mmHg as [TBS] increased to greater than 300 mM [7].
• In gallbladder bile, respective ranges were as follows: pH, 5.72-7.29; PCO2, 36-101 mmHg; [TCO2], 1.21-15.5 mM; [TBS], 150-305 mM; and [Na], 199-266 mM [7].
• Possible roles for the function of the sal1 gene in aleurone signaling, including a defect in endosome trafficking, are discussed [8].
• The sal1 gene encodes a homologue of the human Chmp1 gene, a member of the conserved family of the class E vacuolar protein sorting genes implicated in membrane vesicle trafficking [8].

Chemical compound and disease context of SALL1

• Estrogen mainly induces the increase of TBS and androgen receptor mRNA in uterine endometrium and leiomyoma [9].
• X-chromatin body (XCB) frequencies in oral mucosa were investigated in 14 female patients with the simple non-salt-losing form of congenital virilizing adrenal hyperplasia (CVAH) due to 'partial' 21-hydroxylase deficiency (CVAH-type I), using toluidine blue (TBS) and Feulgen's stains (FS) [10].

Biological context of SALL1

• Mutations in the SALL1 gene on chromosome 16q12.1 cause Townes-Brocks syndrome (TBS) [11].
• Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS [12].
• To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations [12].
• In transient transfection assays, SALL1 promoter activity was higher in HEK-293 human kidney cells and COS-7 monkey kidney cells than in NIH-3T3 fibroblasts, consistent with its role in kidney development [13].
• Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development [13].

Anatomical context of SALL1

• SALL1 has recently been shown to localize to chromocenters and other heterochromatin foci in murine fibroblasts and to interact with the telomere-repeat-binding factor TRF1/PIN2 [11].
• Using epifluorescence and confocal microscopy it could be shown that a GFP-SALL1 fusion protein localizes to chromocenters and smaller heterochromatin foci in transiently transfected NIH-3T3 cells [3].
• In the human pituitary, SALL1 protein expression was limited to the adenohypophysis, where it colocalized to those cells producing GH and the gonadotropins, LH and FSH [14].
• SALL1 protein expression was observed in various adult and fetal tissues which elaborate reproductive endocrine hormones [14].
• The SALL1 protein was also shown here to be highly expressed in trophoblast tumors, which overproduce sex hormones [14].

Associations of SALL1 with chemical compounds

• Mutation of lysine 1086 of SALL1 to arginine abrogates SALL1 sumoylation, suggesting the presence of a polymeric SUMO-1 chain in the wild type state [11].
• Six different SALL1 polymorphisms were identified in the course of the present study, three of which are clustered in a particular region of the gene that encodes a stretch of serine residues [15].
• Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here [16].
• Binding was monitored by the change in fluorescence anisotropy at 25 degrees C and pH 7.4 in 0.02 M Tris buffer, alone (TB) or with 0.15M NaCl (TBS) [17].
• Compared to controls, DLB brains accumulate significantly greater amounts of sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble alpha SN but levels of TBS-soluble alpha SN did not change [18].

Regulatory relationships of SALL1

• Utilizing a luciferase reporter gene assay, endogenous or exogenously added SIX1 activated the SALL1 promoter [13].
• Hsal 1 is related to kidney and gonad development and is expressed in Wilms tumor [19].

Other interactions of SALL1

• The interaction of SALL1 and UBE2I was confirmed in a glutathione S-transferase (GST) pull-down experiment [11].
• Interaction of the developmental regulator SALL1 with UBE2I and SUMO-1 [11].
• Specifically, there is overlap of clinical features with other conditions, most notably Holt-Oram syndrome, a condition resulting from mutation of the TBX5 locus and Townes-Brocks syndrome, known to be caused by mutations in the SALL1 gene [2].
• Two human sal-like genes have been isolated so far, SALL1 on chromosome 16q12.1 and SALL2 on chromosome 14q11.1-q12 [20].
• We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome [12].

Analytical, diagnostic and therapeutic context of SALL1

• Molecular cloning of a SALL1-related pseudogene and mapping to chromosome Xp11.2 [21].
• Mutations in SALL1, a gene mapping to 16q12.1, were identified as a cause for TBS [3].
• Sequence comparison, Northern blot hybridization as well as the conserved chromosome location on the homologous mouse chromosome indicate that we have indeed isolated the murine homolog of SALL1 [22].
• Detection of heterozygous SALL1 deletions by quantitative real time PCR proves the contribution of a SALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome [23].
• In situ hybridization experiments reveal that the sal1 gene is ubiquitously expressed in vegetative as well as zygotic grain tissues, with no difference being detected between aleurone cells and starchy endosperm cells [8].

References