Details for: KRT74

Gene ID: 121391

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: KRT74

Ensembl ID: ENSG00000170484

Description: keratin 74

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • suprabasal keratinocyte CL4033013
    CSI 14.87
    rCSI 24.27%
    PRS 96.53
  • basal cell of epidermis CL0002187
    CSI 4.63
    rCSI 8.2%
    PRS 94.96

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Size: Proportional to Target Cell CSI magnitude
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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Analyzed for its specificity of expression (CSI Z-Score), [KRT74](/details-gene/121391) is a type II keratin that functions as a structural protein primarily involved in the formation of the hair shaft and epidermis. Its expression is highly restricted to keratinocytes, particularly those in the suprabasal layers. Clinically, mutations in [KRT74](/details-gene/121391) are well-documented as a cause of hereditary hair disorders, including autosomal dominant woolly hair and hypotrichosis ([PubMed: 20346438](https://pubmed.ncbi.nlm.nih.gov/20346438/), [PubMed: 21188418](https://pubmed.ncbi.nlm.nih.gov/21188418/)), and a rare autosomal recessive hair and nail ectodermal dysplasia ([PubMed: 24714551](https://pubmed.ncbi.nlm.nih.gov/24714551/)). ## Cellular Roles and Expression Landscape The expression profile of [KRT74](/details-gene/121391), when analyzed for specificity, highlights its role as a highly specialized cytoskeletal component. In the **Overall** context, its expression is almost exclusively confined to [suprabasal keratinocyte](/details-cell/CL4033013) and [basal cell of epidermis](/details-cell/CL0002187). This extreme cell-type restriction is underscored by a maximal Effect Size (deltaVal: 1.00) for both cell types, indicating that its expression in these cells is significantly higher than the average expression across all other cell populations. While the CSI (Z-SCORE) itself is 0.00 with a non-significant p-value, this is likely an artifact of its highly restricted expression pattern skewing the statistical distribution. The high Percentile Rank Score (PRS: >96% for suprabasal keratinocytes) confirms that, relative to all other genes, [KRT74](/details-gene/121391) ranks among the most specific markers for this cell lineage. This finding is consistent with literature identifying it as an inner-root-sheath-specific type II keratin in human hair follicles ([PubMed: 12648212](https://pubmed.ncbi.nlm.nih.gov/12648212/)). Its role appears critical for establishing the structural integrity and texture of hair, as mutations disrupting its function lead directly to hair defects ([PubMed: 20346438](https://pubmed.ncbi.nlm.nih.gov/20346438/)). ## Pathways and Molecular Function The molecular functions of [KRT74](/details-gene/121391) align perfectly with its specific expression in keratinocytes. It is a core participant in biological processes essential for epithelial integrity, including '[Intermediate filament cytoskeleton organization](/details-go/GO:0045104)' and, most notably, '[Keratinization](/details-go/GO:0031424)'. Its involvement is further detailed in Reactome pathways such as '[Keratinization](/reactome/R-HSA-6805567)' and '[Formation of the cornified envelope](/reactome/R-HSA-6809371)', which are the terminal differentiation processes of epidermal keratinocytes that create the protective outer layer of the skin. As a structural molecule, [KRT74](/details-gene/121391) is a key component of the '[Keratin filament](/details-go/GO:0045095)' network within the cytoplasm. The annotation for '[Extracellular exosome](/details-go/GO:0070062)' is intriguing, suggesting a potential, less-characterized role for [KRT74](/details-gene/121391) or its fragments in intercellular communication during epidermal stratification. Its function as a type II keratin necessitates heterodimerization with a type I keratin partner, such as K25-K28 in the inner root sheath, to form the fundamental building blocks of the hair shaft ([PubMed: 12648212](https://pubmed.ncbi.nlm.nih.gov/12648212/), [PubMed: 16874310](https://pubmed.ncbi.nlm.nih.gov/16874310/)). ## Research Directions The highly specific expression of [KRT74](/details-gene/121391) in keratinocytes, coupled with its direct link to heritable hair and nail disorders, presents several avenues for future investigation. The distinction between dominant and recessive disease phenotypes originating from the same gene suggests complex pathomechanisms that warrant further exploration. ### Testable Hypotheses 1. **Hypothesis:** The allelic heterogeneity in [KRT74](/details-gene/121391)-related disorders (dominant woolly hair vs. recessive hair/nail dysplasia) is due to distinct structural consequences. Dominant-negative mutations likely disrupt keratin filament assembly by acting as "poison pills" within the cytoskeleton of the inner root sheath, whereas recessive loss-of-function mutations lead to a complete absence of the protein, affecting a broader differentiation program in both hair follicle and nail matrix keratinocytes. * **Experimental Approach:** Generate keratinocyte cell lines expressing either a known dominant-negative or a null [KRT74](/details-gene/121391) allele using CRISPR/Cas9. Analyze cytoskeletal architecture using super-resolution microscopy and assess filament network dynamics with fluorescence recovery after photobleaching (FRAP). Concurrently, perform RNA-sequencing on these models to identify divergent effects on keratinocyte differentiation pathways. 2. **Hypothesis:** The presence of [KRT74](/details-gene/121391) in extracellular exosomes represents a novel signaling mechanism where differentiating suprabasal keratinocytes communicate with cells in the granular layer to coordinate the timing of cornification and barrier formation. * **Experimental Approach:** Isolate exosomes from primary human keratinocyte cultures at various stages of calcium-induced differentiation. Use mass spectrometry to quantify [KRT74](/details-gene/121391) abundance in the exosomal fraction. Apply these [KRT74](/details-gene/121391)-containing exosomes to recipient keratinocyte cultures and measure the expression of terminal differentiation markers like Loricrin and Filaggrin via qPCR and immunofluorescence. 3. **Hypothesis:** [KRT74](/details-gene/121391) acts as a key determinant of hair shaft texture by modulating the mechanical properties of the inner root sheath (IRS). Its disruption not only causes the 'woolly' phenotype but also alters the biomechanical resilience of the hair fiber. * **Experimental Approach:** Develop a mouse model with a KRT74 mutation orthologous to one found in human woolly hair syndrome. Perform nanoindentation and tensile strength tests on individual hair fibers from these mice compared to wild-type controls. Correlate these mechanical properties with ultrastructural changes in the IRS and hair shaft, as observed by transmission electron microscopy. ### Therapeutic Potential Given its cell-type-specific expression and monogenic disease association, [KRT74](/details-gene/121391) is an attractive target for gene-based therapies. For recessive hair/nail dysplasia caused by loss-of-function, a topical gene replacement therapy using AAV or lipid nanoparticle delivery of a functional [KRT74](/details-gene/121391) coding sequence to the nail matrix or hair follicle could be envisioned. For dominant-negative mutations, an allele-specific siRNA or antisense oligonucleotide approach could selectively silence the mutant allele, restoring normal keratin filament assembly. The high specificity of expression naturally limits the risk of off-target effects in other organ systems.

Genular Protein ID: 2966798819

Symbol: K2C74_HUMAN

Name: Keratin, type II cytoskeletal 74

UniProtKB Accession Codes:

Q7RTS7 B5MD61 Q86Y45

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 Ensembl 1 ExpressionAtlas 1 GO 9 Gene3D 3 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 7 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OpenTargets 1 Orphanet 3 OrthoDB 1 PANTHER 2 PRIDE 1 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 12648212

Title: K6irs1, K6irs2, K6irs3, and K6irs4 represent the inner-root-sheath-specific type II epithelial keratins of the human hair follicle.

PubMed ID: 12648212

DOI: 10.1046/j.1523-1747.2003.12087.x

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

PubMed ID: 11683385

Title: Genes for intermediate filament proteins and the draft sequence of the human genome: novel keratin genes and a surprisingly high number of pseudogenes related to keratin genes 8 and 18.

PubMed ID: 11683385

DOI: 10.1242/jcs.114.14.2569

PubMed ID: 16874310

Title: K25 (K25irs1), K26 (K25irs2), K27 (K25irs3), and K28 (K25irs4) represent the type I inner root sheath keratins of the human hair follicle.

PubMed ID: 16874310

DOI: 10.1038/sj.jid.5700494

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 20346438

Title: Autosomal-dominant woolly hair resulting from disruption of keratin 74 (KRT74), a potential determinant of human hair texture.

PubMed ID: 20346438

DOI: 10.1016/j.ajhg.2010.02.025

PubMed ID: 21188418

Title: Novel mutations in the keratin-74 (KRT74) gene underlie autosomal dominant woolly hair/hypotrichosis in Pakistani families.

PubMed ID: 21188418

DOI: 10.1007/s00439-010-0938-9

PubMed ID: 24714551

Title: Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

PubMed ID: 24714551

DOI: 10.1371/journal.pone.0093607

Sequence Information:

  • Length: 529
  • Mass: 57865
  • Checksum: CE81527DD4825CBF
  • Sequence:
    • MSRQLNIKSS GDKGNFSVHS AVVPRKAVGS LASYCAAGRG AGAGFGSRSL YSLGGNRRIS 
FNVAGGGVRA GGYGFRPGSG YGGGRASGFA GSMFGSVALG PACLSVCPPG GIHQVTVNKS 
LLAPLNVELD PEIQKVRAQE REQIKVLNDK FASFIDKVRF LEQQNQVLET KWELLQQLDL 
NNCKKNLEPI LEGYISNLRK QLETLSGDRV RLDSELRSMR DLVEDYKKRY EVEINRRTTA 
ENEFVVLKKD ADAAYAVKVE LQAKVDSLDK EIKFLKCLYD AEIAQIQTHA SETSVILSMD 
NNRDLDLDSI IAEVRMHYEE IALKSKAEAE ALYQTKIQEL QLAASRHGDD LKHTRSEMVE 
LNRLIQRIRC EIGNVKKQRA SLETAIADAE QRGDNALKDA QAKLDELEGA LHQAKEELAR 
MLREYQELMS LKLALDMEIA TYRKLLEGEE CRMSGENPSS VSISVISSSS YSYHHPSSAG 
VDLGASAVAG SSGSTQSGQT KTTEARGGDL KDTQGKSTPA SIPARKATR