Alternative titles; symbolsWILLIAMS-BEUREN SYNDROME CHROMOSOME REGION 14; WBSCR14MONDO FAMILY, MEMBER B; MONDOBCARBOHYDRATE RESPONSE ELEMENT-BINDING PROTEIN, RAT...
Alternative titles; symbols
HGNC Approved Gene Symbol: MLXIPL
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:73,593,200-73,624,521 (from NCBI)
▼ Cloning and Expression
Williams-Beuren syndrome (WBS; 194050) is a multisystem developmental disorder caused by the deletion of contiguous genes at chromosome 7q11.23. A common interval that includes as many as 17 genes is deleted in most patients. Meng et al. (1998) constructed a physical map encompassing the 1.5-Mb region that is commonly deleted in WBS. They identified 3 genes within this region, including WBSCR14, which they designated WS-bHLH. By EST database searching, sequencing, and screening of a human fetal brain cDNA library, they isolated a partial WBSCR14 cDNA encoding a protein belonging to the basic helix-loop-helix leucine-zipper family of transcription factors.
De Luis et al. (2000) fully characterized the WBSCR14 gene. They identified 2 intragenic polymorphic dinucleotide repeats and used them to verify hemizygosity in WBS patients. They found that the WBSCR14 cDNA encodes an 852-amino acid protein which, in addition to the bHLH-ZIP motif, has a bipartite nuclear localization signal (NLS). Northern blot analysis detected a 4.2-kb transcript predominantly in adult liver and at late stages of fetal development. De Luis et al. (2000) also cloned the mouse homolog. Given that other bHLH-ZIP proteins are dose sensitive and based on the putative function of WBSCR14 as a transcription factor, de Luis et al. (2000) suggested that hemizygosity at this locus may be involved in some features of WBS.
Kawaguchi et al. (2002) cloned Chrebp from rat liver. The rat Chrebp protein shares approximately 94% and 82% identity with mouse and human WBSCR14, respectively.
▼ Gene Function
Cairo et al. (2001) found that WBSCR14 was expressed in multiple tissues, including regions of the brain and the intestinal tract. WBSCR14 formed heterodimers with the bHLH-ZIP protein Mlx (602976) to bind the DNA sequence CACGTG. Like Max (154950), Mlx has no intrinsic transcriptional activity, but its association with Mad1 (602686), Mad4, Mnt (603039), or WBSCR14 can repress E-box-dependent transcription. Preliminary results suggested a possible role of WBSCR14 in growth control. The authors hypothesized that the Max-like bHLH-ZIP protein, Mlx, is a key element of a transcription factor network, and that WBSCR14 may contribute to some aspects of the WBS pathology.
Kawaguchi et al. (2001) noted that rat Chrebp is essential for activation of the liver pyruvate kinase gene (PKLR; 609712). They stated that Chrebp is activated by high glucose and is inhibited by cAMP. By mutation analysis of mouse Chrebp, Kawaguchi et al. (2001) demonstrated that the N-terminal NLS and the C-terminal bHLH and leucine zipper domains were essential for transcription of a reporter gene from the PKL promoter in transfected rat hepatocytes. These 2 domains were targets for regulation by cAMP and glucose. Kawaguchi et al. (2001) found that cAMP-dependent protein kinase (see 601639) phosphorylated ser196 near the NLS, which inactivated nuclear import of Chrebp, and thr666 near the bHLH domain, which dissociated Chrebp from DNA and inactivated PKL transcription. On the other hand, high glucose stimulated dephosphorylation, leading to translocation of Chrebp from the cytosol into the nucleus, where dephosphorylation led to DNA binding.
Kawaguchi et al. (2002) found that acetate and fatty acids inhibited the glucose-induced transcription of PKL in Chrebp-transfected rat hepatocytes. Inhibition was associated with a significant increase in cytosolic AMP and activation of AMPK (see 602739). They determined that AMPK phosphorylated Chrebp on ser568, resulting in loss of DNA binding.
Several endocrine phenotypes, in particular impaired glucose tolerance and silent diabetes, have been described in Williams-Beuren syndrome. A heterodimeric complex consisting of WBSCR14 and the MAX-like protein (MLX; 602976), binds and activates, in a glucose-dependent manner, carbohydrate response element (ChoRE) motifs in the promoter of lipogenic enzymes. Merla et al. (2004) identified 5 novel WBSCR14-interacting proteins, 4 14-3-3 isotypes (beta, 601289; gamma, 605356; zeta, 601288; and theta, 609009) and NIF3L1 (605778), which form a single polypeptide complex in mammalian cells. WBSCR14 was exported actively from the nucleus through a CRM1-dependent mechanism. This translocation was contingent upon the ability to bind 14-3-3. The authors proposed that through this mechanism, the 14-3-3 isotypes may directly affect the WBSCR14:MLX complexes, which may activate the transcription of lipogenic genes.
Herman et al. (2012) reported that adipose tissue GLUT4 (138190) regulates the expression of CHREBP, a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose CHREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. Herman et al. (2012) found a new mechanism for glucose regulation of CHREBP: glucose-mediated activation of the canonical CHREBP isoform (CHREBP-alpha) induces expression of a novel, potent isoform (CHREBP-beta) that is transcribed from an alternative promoter. CHREBP-beta expression in human adipose tissue predicts insulin sensitivity.
▼ Gene Structure
De Luis et al. (2000) determined that the WBSCR14 gene contains 17 exons and spans 33 kb.
Meng et al. (1998) mapped the WBSCR14 gene to the WBS deletion region on chromosome 7q11.23. De Luis et al. (2000) mapped the mouse Wbscr14 gene to chromosome 5 in a region of conserved synteny with human 7q11.23.