FHL1: Four and a Half LIM Domains 1
A key regulator of muscle structure, sarcomere integrity, and transcriptional coactivation, with mutations linked to myopathies and cardiomyopathies.
Gene Information Card
| Symbol | FHL1 |
|---|---|
| Full Name | Four and a Half LIM Domains 1 |
| Gene Type | Protein coding |
| Chromosomal Location | Xq26.3 |
| NCBI Gene ID | 2273 ncbi.nlm.nih.gov/gene/2273 |
| Ensembl ID | ENSG00000122218 |
| UniProt ID | Q13642 |
| OMIM ID | 300163 |
| HGNC ID | 3702 |
| Aliases | SLIM1, SLIM, FHL-1, KYO-T, RBMX1A |
Description
FHL1 (Four and a Half LIM Domains 1) encodes a member of the four-and-a-half-LIM-only protein family. The protein contains four and a half LIM domains (zinc-binding motifs) and is predominantly expressed in skeletal and cardiac muscle. FHL1 acts as a scaffold protein, localizing to the sarcomere and Z-disc, and functions in transcriptional regulation, myoblast differentiation, and mechanotransduction. Mutations in FHL1 cause several X-linked myopathies and cardiomyopathies, including reducing body myopathy, scapuloperoneal myopathy, and X-linked dilated cardiomyopathy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Reducing body myopathy (RBM) | Missense mutations in LIM domains disrupt zinc coordination, leading to protein aggregation and sarcomeric disorganization. | ClinVar, OMIM #300718 |
| X-linked myopathy with postural muscle atrophy (XMPMA) | Mutations affecting the C-terminal LIM domain impair protein stability and interaction with sarcomeric proteins. | OMIM #300696 |
| Scapuloperoneal myopathy (SPM) | Dominant-negative mutations in FHL1 alter Z-disc structure and cause progressive muscle weakness. | ClinVar, OMIM #300695 |
| X-linked dilated cardiomyopathy (XLDC) | Loss-of-function mutations reduce FHL1 expression, compromising sarcomere integrity and cardiac contractility. | OMIM #300163, ClinVar |
| Emery-Dreifuss muscular dystrophy (EDMD)-like phenotype | FHL1 mutations disrupt nuclear envelope and sarcomere linkage, mimicking EDMD. | ClinVar, OMIM #300163 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal muscle | 128.5 | High |
| Heart | 95.2 | High |
| Smooth muscle | 12.3 | Medium |
| Lung | 3.1 | Low |
| Liver | 1.2 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Skeletal muscle myoblasts (HSMM) | 85.4 | High expression; decreases upon differentiation |
| Cardiomyocytes (AC16) | 72.1 | High expression |
| HeLa | 2.3 | Low expression |
| HEK 293 | 1.8 | Low expression |
| A549 | 0.9 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.275G>A (p.Cys92Tyr) | Missense | Reported in RBM | Disrupts LIM2 domain zinc binding; causes protein aggregation |
| c.448C>T (p.Arg150Trp) | Missense | Reported in XMPMA | Impairs protein stability and sarcomere localization |
| c.520T>C (p.Cys174Arg) | Missense | Reported in SPM | Dominant-negative effect; disrupts Z-disc integrity |
| c.1A>G (p.Met1Val) | Start loss | Rare | Loss of translation initiation; complete loss of function |
| c.676_678del (p.Lys226del) | In-frame deletion | Reported in XLDC | Deletion in LIM4 domain; reduced protein expression |
Mutation functional classification
Loss of Function (LOF)
Nonsense, frameshift, and start-loss mutations that abolish FHL1 protein expression or disrupt critical LIM domain structure, leading to haploinsufficiency in X-linked dilated cardiomyopathy.
Gain of Function (GOF)
Not clearly established; some missense mutations in reducing body myopathy may confer toxic gain-of-function through aberrant aggregation.
Dominant Negative (DN)
Missense mutations in the C-terminal LIM domains (e.g., p.Cys174Arg) that produce a stable but dysfunctional protein that interferes with wild-type FHL1 function, observed in scapuloperoneal myopathy.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Integrin signaling pathway (Reactome: R-HSA-446728)
• Striated muscle contraction (Reactome: R-HSA-397014)
• Sarcomere organization (Reactome: R-HSA-5250913)
• Transcriptional regulation by FHL1 (PMID: 15616578)
Protein Summary
FHL1 is a 32 kDa protein composed of four and a half LIM domains, each containing two zinc fingers. It is highly expressed in skeletal and cardiac muscle, where it localizes to the Z-disc and sarcomere. FHL1 functions as a scaffold, interacting with structural proteins (e.g., titin, myosin-binding protein C) and transcription factors (e.g., SRF, MyoD). It regulates myoblast differentiation, muscle growth, and mechanotransduction. Mutations in FHL1 cause a spectrum of X-linked muscle diseases, including reducing body myopathy, scapuloperoneal myopathy, and dilated cardiomyopathy. The protein also has roles in cancer, where altered expression is observed in some tumors.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FHL1 Knockout HEK293 Cell Line | EDJ-KQ462 | Human | 2273 | Details Get a Quote |
| FHL1 Knockout HCT 116 Cell Line | EDJ-KQ18006 | Human | 2273 | Details Get a Quote |
| FHL1 Knockout HeLa Cell Line | EDJ-KQ18357 | Human | 2273 | Details Get a Quote |
| FHL1 Knockout A-549 Cell Line | EDJ-KQ18772 | Human | 2273 | Details Get a Quote |
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