Townes-Brocks syndrome: Detection of a SALL1 mutation hot spot and evidence for a position effect in one patient

Abstract

Townes-Brocks syndrome (TBS) is an autosomal dominant developmental disorder characterized by anal and thumb malformations and by ear anomalies that can affect the three compartments and usually lead to hearing loss. The gene underlying TBS, SALL1, is a human homolog of the Drosophila spalt gene which encodes a transcription factor. A search for SALL1 mutations undertaken in 11 unrelated affected individuals (five familial and six sporadic cases) led to the detection of mutations in nine of them. One nonsense and six different novel frameshift mutations, all located in the second exon, were identified. Together with the previously reported mutations [Kohlhase et al., 1999], they establish that TBS results from haploinsufficiency. The finding of de novo mutations in the sporadic cases is consistent with the proposed complete penetrance of the disease. Moreover, the occurrence of the same 826C>T transition in a CG dimer, in three sporadic cases from the present series and three sporadic cases from the other series [Kohlhase et al., 1999] (i.e., six of the eight mutations identified in sporadic cases), reveals the existence of a mutation hotspot. 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. Finally, the chromosome 16 breakpoint of a t(5;16)(p15.3;q12.1) translocation carried by a TBS-affected individual was mapped at least 180 kb telomeric to SALL1, thus indicating that a position effect underlies the disease in this individual.

SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype

“…nucleotides 1351-1497) (Kohlhase et al, 1999;Marlin et al, 1999). Our results reported here confirm this observation.…”

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

“…In humans, the SALL gene family is involved in normal development, as well as in tumorigenesis. [126][127][128][129][130][131][132] During normal hematopoiesis SALL4 isoforms are expressed in the CD34 þ hematopoietic stem and progenitor cell population, and they are rapidly turned off (SALL4B), respectively, downregulated (SALL4A) in normal human bone marrow and peripheral blood. 125 SALL4 isoforms were constitutively expressed on the mRNA and the protein level in all primary human AML samples tested, as well as in all AML cell lines.…”

SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice

“…21 In humans, the SALL gene family is involved in normal development, as well as tumorigenesis. 19,[22][23][24][25][26][27] SALL proteins belong to a group of C 2 H 2 zinc finger transcription factors characterized by multiple finger domains distributed over the entire protein. 28 During the tracheal development of Drosophila, spalt is an activated downstream target of Wingless, a Wnt ortholog.…”