Human FHL2 gene spans around 80kb of genomic DNA on the chromosome 2q12-q14 in telomere-to-centromere orientation. FHL2 promoter contains putative transcription factor binding sites for SRF (serum response factor), NKX2-5, MEF-2, E2F and AP-1 (activator protein-1).

Four transcript variants of FHL2 genes have been reported in Entrez Gene (NCBI). These alternative spliced transcripts are 1.55-1.91 kb in length, and differ in the 5-UTR only.

No pseudogenes for FHL2 are known.

The open reading frame encodes a 279 amino acid protein with an estimated molecular weight of 32.2kDa. FHL2 protein constitutes four and a half N-terminal LIM domains. The four complete LIM domains extend from amino acid 40-92, 100-153, 162-217 and 220-275.

In human tissues, FHL2 expression is the most abundant in adult heart and ovary, and of low level in brain, lung, liver, kidney and intestine. FHL2 is initially identified as a downregulated gene in human rhabdomyosarcoma cells. However, elevated FHL2 expression is detected in other cancers, including hepatocellular carcinoma, glioblastoma, breast, prostate, ovarian, and gastrointestinal cancers.

Cytoplasm and nucleus.

At tissue level, FHL2 plays important roles in the development of cardiac circulatory system and placenta. It also induces osteoblast and myoblast differentiation. At cellular level, FHL2 participates in various processes, including cell survival, adhesion, motility, transcription and signal transduction. At molecular level, the LIM domains of FHL2 are double zinc finger motifs that physically interact with partner proteins to modulate RNA splicing, DNA replication and repair. It also functions as a transcriptional co-activator for androgen receptor, AP-1, CREB (cAMP response element binding protein), CREM (cAMP response element modulator), BRCA1 (breast cancer 1), WT-1 (wilms tumor), and NF-kB (nuclear factor-kB). Moreover, FHL2 is a transcriptional co-suppressor for ERK2 (extracellular signal regulated kinase 2), SRF and FOXO1 (forkhead box O1).

FHL2 belongs to the four-and-a-half-LIM-only protein family, which includes FHL1, FHL2, FHL3, FHL4 and FHL5 (ACT). Human FHL2 amino acid sequence is 48.2% identical with FHL1, 53.4% with FHL3, 48.4% with mouse FHL4, and 59.1% with FHL5. Orthologs of human FHL2 are found in macaque, mouse, rat, bovine, dog, chicken, frog, zebrafish, amphioxis, drosophila and C. elegans.

G142A missense mutation, corresponding to Gly48Ser within the first LIM domain, is identified in heterozygous state in a 49-years-old female dilated cardiomyopathy (DCM) patient. This mutation abrogates the binding of FHL2 with titin/connectin, and in turn impairs the abnormal recruitment of metabolic enzymes to cardiac sarcomere (Arimura et al., 2007).