ALX4 Gene: Aristaless-Like Homeobox 4
Key regulator of craniofacial and limb development; mutations linked to parietal foramina and frontonasal dysplasia.
Gene Information Card
| Symbol | ALX4 |
|---|---|
| Full Name | Aristaless-like homeobox 4 |
| Gene Type | Protein-coding |
| Chromosomal Location | 11p11.2 |
| NCBI Gene ID | 60529 ncbi.nlm.nih.gov/gene/60529 |
| Ensembl ID | ENSG00000152818 |
| UniProt ID | Q9H161 |
| OMIM ID | 605422 |
| HGNC ID | 400 |
| Aliases | FND3, PFM2, KIAA1788 |
Description
ALX4 encodes a paired-class homeodomain transcription factor essential for craniofacial, limb, and skeletal development. It regulates mesenchymal cell proliferation and differentiation during embryogenesis. Loss-of-function mutations cause parietal foramina 2 (PFM2) and frontonasal dysplasia 3 (FND3). The protein binds DNA via its homeodomain and interacts with other transcription factors to control target gene expression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Parietal foramina 2 (PFM2) | Loss-of-function mutations in ALX4 impair osteoblast differentiation, leading to defective ossification of parietal bones. | OMIM #609597; ClinVar; multiple familial cases reported. |
| Frontonasal dysplasia 3 (FND3) | Biallelic loss-of-function mutations disrupt craniofacial patterning, causing hypertelorism, cleft lip/palate, and nasal defects. | OMIM #613456; ClinVar; homozygous/compound heterozygous variants. |
| Potocki-Shaffer syndrome (contiguous gene deletion) | Heterozygous deletion of 11p11.2 including ALX4 and EXT2 leads to parietal foramina, multiple exostoses, and intellectual disability. | OMIM #601224; ClinVar; large deletions confirmed. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skin | 0.2 | Not detected |
| Bone marrow | 0.1 | Not detected |
| Brain (cerebellum) | 0.0 | Not detected |
| Heart | 0.0 | Not detected |
| Kidney | 0.0 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HUVEC (umbilical vein endothelial) | 0.0 | No expression |
| HeLa (cervical carcinoma) | 0.0 | No expression |
| K562 (leukemia) | 0.0 | No expression |
| MCF7 (breast carcinoma) | 0.0 | No expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.226C>T (p.Arg76*) | Nonsense | Rare (found in PFM2 families) | Loss-of-function; premature stop codon truncates homeodomain. |
| c.296_297delAG (p.Glu99Valfs*10) | Frameshift | Rare (FND3) | Loss-of-function; frameshift leads to nonsense-mediated decay. |
| c.467G>A (p.Arg156His) | Missense | Rare (PFM2) | Loss-of-function; disrupts DNA-binding affinity. |
| c.1A>G (p.Met1?) | Start loss | Rare (FND3) | Loss-of-function; abolishes translation initiation. |
Mutation functional classification
Loss of Function (LOF)
Majority of ALX4 mutations are loss-of-function (nonsense, frameshift, start loss, missense in homeodomain), leading to haploinsufficiency (PFM2) or biallelic deficiency (FND3).
Gain of Function (GOF)
No gain-of-function mutations reported in ALX4.
Dominant Negative (DN)
No dominant-negative mechanisms described for ALX4.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity (GO:0003700) | • RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978) |
| • homeodomain binding (GO:0045329) | • regulation of transcription by RNA polymerase II (GO:0006357) |
| • anterior/posterior pattern specification (GO:0009952) | • skeletal system development (GO:0001501) |
| • craniofacial development (GO:0060322) | • limb development (GO:0060173) |
Pathways
• Hedgehog signaling pathway (Reactome R-HSA-5358351)
• Transcriptional regulation by RUNX2 (Reactome R-HSA-8939243)
• Osteoblast differentiation (KEGG hsa04350)
Protein Summary
ALX4 is a 401-amino acid homeodomain transcription factor (UniProt Q9H161) expressed primarily in developing mesenchyme of the craniofacial region, limbs, and somites. The protein contains a paired-class homeodomain (residues 131-190) that mediates sequence-specific DNA binding. ALX4 functions as a transcriptional repressor or activator depending on context, and it interacts with MSX1, MSX2, and DLX5 to regulate bone and cartilage formation. In adults, expression is very low or absent in most tissues.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ALX4 Knockout HEK293 Cell Line | EDJ-KQ12158 | Human | 60529 | Details Get a Quote |
| ALX4 Knockout HeLa Cell Line | EDJ-KQ56984 | Human | 60529 | Details Get a Quote |
| ALX4 Knockout A-549 Cell Line | EDJ-KQ65486 | Human | 60529 | Details Get a Quote |
| ALX4 Knockout HCT 116 Cell Line | EDJ-KQ73924 | Human | 60529 | Details Get a Quote |
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