TCHH

Summary

TCHH (trichohyalin, HGNC:11791) is a protein-coding gene on chromosome 1q21.3, encoding Trichohyalin (Q07283). Intermediate filament-associated protein that associates in regular arrays with keratin intermediate filaments (KIF) of the inner root sheath cells of the hair follicle and the granular layer of the epidermis.

The protein encoded by this gene forms crosslinked complexes with itself and keratin intermediate filaments to provide mechanical strength to the hair follicle inner root sheath. The encoded protein also is important for structural integrity of the filiform papillae of the tongue. Defects in this gene are a cause of uncombable hair syndrome.

Source: NCBI Gene 7062 — RefSeq curated summary.

At a glance

• Gene–disease (curated): uncombable hair syndrome 3 (Limited, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 473 total — 3 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_007113

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11791
Approved symbol	TCHH
Name	trichohyalin
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000159450
Ensembl biotype	protein_coding
OMIM	190370
Entrez	7062

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000614923

RefSeq mRNA: 1 — MANE Select: NM_007113 NM_007113

CCDS: CCDS41396

Canonical transcript exons

ENST00000614923 — 3 exons

Exon	Start	End
ENSE00001447994	152106317	152113078
ENSE00003744354	152113943	152114111
ENSE00003745138	152115391	152115444

Expression profiles

Bgee: expression breadth ubiquitous, 101 present calls, max score 97.35.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2648 / max 314.3512, expressed in 11 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14534	0.2648	11

Top tissues by expression

248 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	97.35	gold quality
tongue squamous epithelium	UBERON:0006919	89.29	gold quality
skin of hip	UBERON:0001554	88.57	gold quality
placenta	UBERON:0001987	80.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.39	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.89	gold quality
sural nerve	UBERON:0015488	69.09	gold quality
nipple	UBERON:0002030	68.44	gold quality
body of tongue	UBERON:0011876	65.70	gold quality
hair follicle	UBERON:0002073	65.50	silver quality
tongue	UBERON:0001723	63.36	gold quality
zone of skin	UBERON:0000014	61.93	gold quality
upper leg skin	UBERON:0004262	61.39	gold quality
spleen	UBERON:0002106	61.05	gold quality
skin of abdomen	UBERON:0001416	59.68	gold quality
skin of leg	UBERON:0001511	58.08	gold quality
endometrium epithelium	UBERON:0004811	57.87	gold quality
cortical plate	UBERON:0005343	56.49	gold quality
endothelial cell	CL:0000115	55.94	gold quality
palpebral conjunctiva	UBERON:0001812	54.90	silver quality
prefrontal cortex	UBERON:0000451	54.58	gold quality
parotid gland	UBERON:0001831	53.81	silver quality
cervix squamous epithelium	UBERON:0006922	52.66	silver quality
superior surface of tongue	UBERON:0007371	51.27	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.81	gold quality
Brodmann (1909) area 46	UBERON:0006483	50.54	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
quadriceps femoris	UBERON:0001377	50.38	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

73 targeting TCHH, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975

Literature-anchored findings (GeneRIF, showing 9)

• BMP-4 signalling activates AHF transcription in hair follicles. (PMID:18643848)
• In human keratinocytes, we found BMP-4 facilitates trichohyalin (THH) transcription, and lamin C plays a key role in the posttranslational stabilization of THH. (PMID:18643848)
• Common variants in the TCHH gene are associated with straight hair in Europeans. (PMID:19896111)
• Data suggest that an immune response to trichohyalin and K16 may have a role in the pathogenesis of the enigmatic disorder. (PMID:20722389)
• The difference between the twoinduced pluripotent stem cell(IPSC) clones in TCHH methylation did not have an obvious effect on its expression in 3D human epidermal equivalent, suggesting that differentiation and tissue formation may mitigate variations in the iPSC methylome. (PMID:27460132)
• To evaluate the relative contribution of these variants, we performed a second genome-wide scan in 709 samples from the Uyghur, an admixed population with both eastern and western Eurasian ancestries. In Uyghurs, both EDAR (rs3827760: P = 1.92 x 10(-12)) and TCHH (rs11803731: P = 1.46 x 10(-3)) are associated with hair straightness, but EDAR (OR 0.415) has a greater effect than TCHH (OR 0.575). (PMID:27487801)
• The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. (PMID:27866708)
• Methylome profiling identifies TCHH methylation in CfDNA as a noninvasive marker of liver metastasis in colorectal cancer. (PMID:34110642)
• Identification of MKI67, TPR , and TCHH Mutations as Prognostic Biomarkers for Patients With Defective Mismatch Repair Colon Cancer Stage II/III. (PMID:37643197)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tchh	ENSMUSG00000052415

Protein

Protein identifiers

Trichohyalin — Q07283 (reviewed: Q07283)

All UniProt accessions (1): Q07283

UniProt curated annotations — full annotation on UniProt →

Function. Intermediate filament-associated protein that associates in regular arrays with keratin intermediate filaments (KIF) of the inner root sheath cells of the hair follicle and the granular layer of the epidermis. It later becomes cross-linked to KIF by isodipeptide bonds. It may serve as scaffold protein, together with involucrin, in the organization of the cell envelope or even anchor the cell envelope to the KIF network. It may be involved in its own calcium-dependent postsynthetic processing during terminal differentiation.

Subunit / interactions. Monomer.

Tissue specificity. Found in the hard keratinizing tissues such as the inner root sheath (IRS) of hair follicles and medulla, and in the filiform papillae of dorsal tongue epithelium.

Post-translational modifications. Substrate of transglutaminase. Some 200 arginines are probably converted to citrullines by peptidylarginine deimidase.

Disease relevance. Uncombable hair syndrome 3 (UHS3) [MIM:617252] A form of uncombable hair syndrome, a condition characterized by scalp hair that is impossible to comb due to the haphazard arrangement of the hair bundles. A characteristic morphologic feature is a triangular to reniform to heart shape on cross-sections, and a groove, canal or flattening along the entire length of the hair. Most individuals are affected early in childhood and the hair takes on a spun-glass appearance with the hair becoming dry, curly, glossy, lighter in color, and progressively uncombable. The hair growth rate can range from slow to normal, and the condition improves with age. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Consists of nine domains. Domain 1 contains two EF-hand calcium-binding domains. Domains 2-4, 6, and 8 are almost entirely alpha-helical, configured as a series of peptide repeats of varying regularity, and are thought to form a single-stranded alpha-helical rod stabilized by ionic interactions. Domain 6 is the most regular and may bind KIF directly by ionic interactions. Domains 5 and 7 are less well organized and may induce folds in the molecule. Domain 9 contains the C-terminus, conserved among different species.

Similarity. Belongs to the S100-fused protein family.

RefSeq proteins (1): NP_009044* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001751	S100/CaBP7/8-like_CS	Conserved_site
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013787	S100_Ca-bd_sub	Domain
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR033200	TCHH	Family
IPR034325	S-100_dom	Domain

Pfam: PF01023

UniProt features (93 total): repeat 23, region of interest 22, compositionally biased region 17, sequence conflict 15, sequence variant 7, binding site 6, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q07283-F1	67.96	0.00

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 32; 62; 64; 66; 68; 73

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope

MSigDB gene sets: 0 (showing top):

GO Biological Process (2): keratinization (GO:0031424), intermediate filament organization (GO:0045109)

GO Molecular Function (3): calcium ion binding (GO:0005509), transition metal ion binding (GO:0046914), metal ion binding (GO:0046872)

GO Cellular Component (3): cornified envelope (GO:0001533), cytosol (GO:0005829), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion binding	2
keratinocyte differentiation	1
multicellular organismal process	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
cation binding	1
plasma membrane	1
cytoplasm	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1571 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCHH	LORICRIN	P23490	977
TCHH	IVL	P07476	977
TCHH	PADI3	Q9ULW8	880
TCHH	S100A10	P08206	846
TCHH	S100A6	P06703	748
TCHH	SPRR1A	P35321	724
TCHH	SPRR3	Q9UBC9	679
TCHH	TTC3	P78477	657
TCHH	FLG	P20930	645
TCHH	FLG2	Q5D862	639
TCHH	SPRR1B	P22528	622
TCHH	RPTN	Q6XPR3	604
TCHH	S100A1	P23297	584
TCHH	PLEC	Q15149	556
TCHH	C4BPA	P04003	556

IntAct

16 interactions, top by confidence:

A	B	Type	Score
CCND1	CDK2	psi-mi:“MI:0914”(association)	0.880
OAZ3	AZIN1	psi-mi:“MI:0914”(association)	0.800
CCND1	CDK1	psi-mi:“MI:0914”(association)	0.640
NSMAF	DUSP14	psi-mi:“MI:0914”(association)	0.530
CCDC127	CETN3	psi-mi:“MI:0914”(association)	0.530
TCHH	LMNA	psi-mi:“MI:0915”(physical association)	0.400
EZR	MACROD2	psi-mi:“MI:0914”(association)	0.350
TBC1D14		psi-mi:“MI:0914”(association)	0.350
BPIFA1	HLA-DPA1	psi-mi:“MI:0914”(association)	0.350
NSMCE1	TCHH	psi-mi:“MI:0914”(association)	0.350
HS1BP3	MPO	psi-mi:“MI:0914”(association)	0.350
CUL4B	CAND2	psi-mi:“MI:0914”(association)	0.350
EFHD1	TCHH	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Proximity Label-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS), TCHH (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YWL9, A0A0J9YY54, A0A1B0GV03, A6NEF3, A6NEM1, A6NI86, A8MZA4, B4DH59, D3YVF0, F6QRE9, H0YKK7, H0YM25, P0C6Y7, P0C7A2, P0DX00, P0DX01, P0DX02, P14590, P21263, P22793, P24587, P24710, P48997, P48998, Q07283, Q0II65, Q0P6D6, Q13342, Q3BBV2, Q4R9C9, Q5W0A0, Q6AXX0, Q6NSX1, Q6P5H2, Q6P902, Q86T75, Q8CHD8, Q8N2N9, Q8N660, Q8N7Z2

Diamond homologs: A6QP92, P20930, P37709, P97347, Q07283, Q2VIS4, Q5D862, Q5QJ38, Q6XPR3, Q9D3P1, Q9UBG3, A7K6Y8, A7K6Y9, O77691, O77791, P02632, P02633, P02634, P02638, P02639, P04163, P04271, P04631, P05109, P05942, P05943, P05964, P06702, P06703, P07091, P08207, P10462, P14069, P22793, P23297, P24479, P24480, P25815, P26447, P27003

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
DNA damage response	5	13.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

473 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	419
Likely benign	44
Benign	5

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2504039	NM_007113.4(TCHH):c.699del (p.Gln234fs)	Likely pathogenic
374835	NM_007113.4(TCHH):c.991C>T (p.Gln331Ter)	Likely pathogenic
4056308	NM_007113.4(TCHH):c.1153_1162del (p.Arg385fs)	Likely pathogenic

SpliceAI

88 predictions. Top by Δscore:

Variant	Effect	Δscore
1:152113077:CT:C	acceptor_gain	0.9900
1:152113937:TCTTA:T	donor_loss	0.9900
1:152113938:CTTAC:C	donor_loss	0.9900
1:152113939:TTACC:T	donor_loss	0.9900
1:152113940:TACC:T	donor_loss	0.9900
1:152113941:A:T	donor_loss	0.9900
1:152113941:AC:A	donor_gain	0.9900
1:152113942:C:CT	donor_loss	0.9900
1:152113942:CC:C	donor_gain	0.9900
1:152113079:C:CC	acceptor_gain	0.9800
1:152113941:A:AC	donor_gain	0.9800
1:152113942:C:CC	donor_gain	0.9800
1:152113081:A:C	acceptor_gain	0.9700
1:152113963:C:A	donor_gain	0.9700
1:152113075:GTCTC:G	acceptor_loss	0.9600
1:152113076:TCT:T	acceptor_gain	0.9600
1:152113077:CTC:C	acceptor_gain	0.9600
1:152113078:TCTA:T	acceptor_loss	0.9600
1:152113078:TCTAT:T	acceptor_gain	0.9600
1:152113079:CTATA:C	acceptor_loss	0.9600
1:152112974:CACTT:C	acceptor_gain	0.9500
1:152113079:C:G	acceptor_gain	0.9500
1:152113075:GTCT:G	acceptor_gain	0.9400
1:152113074:GGTCT:G	acceptor_gain	0.9200
1:152113935:GTTCT:G	donor_loss	0.8900
1:152113936:TTCTT:T	donor_loss	0.8900
1:152113087:A:C	acceptor_gain	0.8700
1:152113081:A:AC	acceptor_gain	0.8500
1:152113090:G:C	acceptor_gain	0.8500
1:152113087:A:AC	acceptor_gain	0.8300

AlphaMissense

12834 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:152113983:A:G	L33P	0.994
1:152113974:A:G	L36P	0.992
1:152112995:G:C	F74L	0.990
1:152112995:G:T	F74L	0.990
1:152112997:A:G	F74L	0.990
1:152113971:A:T	L37H	0.988
1:152114036:G:C	F15L	0.988
1:152114036:G:T	F15L	0.988
1:152114038:A:G	F15L	0.988
1:152112996:A:G	F74S	0.986
1:152113004:G:C	F71L	0.986
1:152113004:G:T	F71L	0.986
1:152113006:A:G	F71L	0.986
1:152113971:A:G	L37P	0.986
1:152112993:A:G	L75P	0.984
1:152112972:G:T	A82D	0.983
1:152113998:A:G	L28S	0.982
1:152112967:C:G	A84P	0.980
1:152113038:A:G	L60P	0.980
1:152111105:C:A	W704C	0.979
1:152111105:C:G	W704C	0.979
1:152112973:C:G	A82P	0.979
1:152107419:T:C	Y1933C	0.978
1:152113958:A:C	F41L	0.978
1:152113958:A:T	F41L	0.978
1:152113959:A:G	F41S	0.978
1:152113960:A:G	F41L	0.978
1:152107416:A:G	I1934T	0.977
1:152107433:G:C	S1928R	0.976
1:152107433:G:T	S1928R	0.976

dbSNP variants (sampled 300 via entrez): RS1000292552 (1:152115936 T>C), RS1000444196 (1:152115658 G>A), RS1000732136 (1:152115216 C>T), RS1002899585 (1:152114485 C>T), RS1003646576 (1:152111312 C>T), RS1003808065 (1:152113145 CAT>C), RS1004540078 (1:152106404 G>C), RS1005490681 (1:152112803 C>A), RS1006249936 (1:152111038 C>T), RS1007032156 (1:152115057 C>T), RS1007457279 (1:152116502 G>C), RS1007470835 (1:152115535 C>T), RS1007776301 (1:152116875 A>G), RS1007926410 (1:152107221 A>T), RS1008249698 (1:152117026 A>C,G)

Disease associations

OMIM: gene MIM:190370 | disease phenotypes: MIM:617252

GenCC curated gene-disease

Disease	Classification	Inheritance
uncombable hair syndrome 3	Limited	Autosomal recessive

Mondo (1): uncombable hair syndrome 3 (MONDO:0014990)

Orphanet (0):

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002212	Curly hair
HP:0002235	Pili canaliculi
HP:0002299	Brittle hair
HP:0011463	Childhood onset
HP:0030056	Uncombable hair

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000519_12	Hair morphology	3.000000e-31
GCST000706_1	Common traits (Other)	2.000000e-42
GCST003474_1	Scalp hair shape	3.000000e-12
GCST006661_183	Male-pattern baldness	1.000000e-10
GCST007563_33	Allergic disease (asthma, hay fever or eczema)	3.000000e-11
GCST007564_24	Asthma or allergic disease (pleiotropy)	5.000000e-12
GCST008916_82	Asthma	5.000000e-27
GCST008916_88	Asthma	1.000000e-25
GCST009718_16	Eczema	1.000000e-64
GCST009798_26	Asthma	2.000000e-21
GCST010605_1	Parent of origin effect on receptive language ability (paternal)	9.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005038	hair morphology
EFO:0005686	receptive language perception
EFO:0005939	parental genotype effect measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	2
Silicon Dioxide	increases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
Tretinoin	increases expression	2
bisphenol F	increases expression	1
sotorasib	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
sodium arsenate	increases abundance, decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
pentanal	increases expression	1
abrine	increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Aldehydes	increases expression	1
Arsenic	decreases expression, increases abundance	1
Copper	decreases expression, affects cotreatment	1
Methapyrilene	decreases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.