We report on two unrelated patients with Townes-Brocks syndrome who share an identical SALL1 mutation (c.3414_3415delAT), who also have endocrine abnormalities.
Taken together, they do not support the correlation of SALL1 deletions with a milder TBS phenotype and highlight a need for more robust clinical phenotyping combined with investigation of mutational mechanism.
We hypothesize that interactions of SHH and SALL1 explain the overlapping features of the family described here and patients with Townes-Brocks syndrome.
Human SALL1 is a homologue of the Drosophila region-specific homeotic gene sal, and is also known as a causative gene for Townes-Brocks syndrome, which is characterized by multi-organ malformations.
In SALL1, a mutant allele causing Townes-Brocks syndrome was unexpectedly resistant to NMD, whereas a different mutation causing a much milder phenotype was susceptible to NMD.
Gene mutations that have dominant inheritance and cause RHD, urinary tract anomalies, and defined extrarenal symptoms have been identified in TCF2 (renal cysts and diabetes syndrome), PAX2 (renal-coloboma syndrome), EYA1 and SIX1 (branchio-oto-renal syndrome), and SALL1 (Townes-Brocks syndrome).
We traced the parental origin of SALL1 mutations in sporadic TBS by analysis of linkage between SALL1 mutations and exonic or intronic polymorphisms in 16 families with 10 different mutations.
We applied quantitative real time PCR to detect and map SALL1 deletions in 240 patients with the clinical diagnosis of TBS, who were negative for SALL1 mutations.Deletions were found in three families.
The SALL1 gene has been associated with the Townes-Brocks Syndrome (TBS), a disorder characterized by multiorgan dysgenesis including renal and genital malformations.
Sequencing of SALL1, the gene mutated in TBS, in four of the eight patients revealed one with a C --> T transition (resulting in a nonsense mutation R276X) at a previously identified mutational "hot spot."
Furthermore, the Hsal 1 gene product may play a part in the pathogenesis of specific neoplasms occurring in these organs in addition to its specific role in Townes-Brocks syndrome.