KAZALD1

Summary

KAZALD1 (Kazal type serine peptidase inhibitor domain 1, HGNC:25460) is a protein-coding gene on chromosome 10q24.31, encoding Kazal-type serine protease inhibitor domain-containing protein 1 (Q96I82). Involved in the proliferation of osteoblasts during bone formation and bone regeneration.

This gene encodes a secreted member of the insulin growth factor-binding protein (IGFBP) superfamily. The protein contains an insulin growth factor-binding domain in its N-terminal region, a Kazal-type serine protease inhibitor and follistatin-like domain in its central region, and an immunoglobulin-like domain in its C-terminal region. Studies of the mouse ortholog suggest that this protein may function in bone development and bone regeneration. This gene is hypomethylated and over-expressed in high-grade glioma compared to low-grade glioma, and thus the hypomethylated gene may be associated with cell proliferation and the shorter survival of patients with high-grade glioma. It is also one of numerous genes found to be deleted in a novel 5.54 Mb interstitial deletion, which is associated with multiple congenital anomalies. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 81621 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 75 total
• MANE Select transcript: NM_030929

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25460
Approved symbol	KAZALD1
Name	Kazal type serine peptidase inhibitor domain 1
Location	10q24.31
Locus type	gene with protein product
Status	Approved
Aliases	FKSG40, FKSG28
Ensembl gene	ENSG00000107821
Ensembl biotype	protein_coding
OMIM	609208
Entrez	81621

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding_CDS_not_defined, 4 protein_coding

ENST00000370200, ENST00000465807, ENST00000470106, ENST00000477267, ENST00000477979, ENST00000608812, ENST00000891380, ENST00000917878, ENST00000952668

RefSeq mRNA: 2 — MANE Select: NM_030929 NM_001319303, NM_030929

CCDS: CCDS7509

Canonical transcript exons

ENST00000370200 — 5 exons

Exon	Start	End
ENSE00001271374	101062542	101063103
ENSE00001452050	101064826	101067059
ENSE00001829416	101061989	101062115
ENSE00003585233	101064261	101064421
ENSE00003659687	101064501	101064648

Expression profiles

Bgee: expression breadth ubiquitous, 176 present calls, max score 89.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.3433 / max 105.9385, expressed in 1167 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106643	2.3338	558
106640	1.6998	681
106638	0.7242	285
106644	0.4872	240
106641	0.3592	215
106639	0.3343	189
106645	0.2770	164
106642	0.1278	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.73	gold quality
spleen	UBERON:0002106	87.80	gold quality
mucosa of transverse colon	UBERON:0004991	84.49	gold quality
apex of heart	UBERON:0002098	83.08	gold quality
parotid gland	UBERON:0001831	83.07	silver quality
calcaneal tendon	UBERON:0003701	82.89	gold quality
tendon	UBERON:0000043	82.16	gold quality
descending thoracic aorta	UBERON:0002345	82.12	gold quality
popliteal artery	UBERON:0002250	81.96	gold quality
tibial artery	UBERON:0007610	81.92	gold quality
aorta	UBERON:0000947	81.50	gold quality
body of stomach	UBERON:0001161	81.41	gold quality
ascending aorta	UBERON:0001496	81.32	gold quality
thoracic aorta	UBERON:0001515	81.16	gold quality
tendon of biceps brachii	UBERON:0008188	80.93	silver quality
stomach	UBERON:0000945	80.02	gold quality
stromal cell of endometrium	CL:0002255	79.78	gold quality
right atrium auricular region	UBERON:0006631	79.69	gold quality
right coronary artery	UBERON:0001625	79.60	gold quality
saliva-secreting gland	UBERON:0001044	78.91	gold quality
minor salivary gland	UBERON:0001830	78.67	gold quality
cardiac atrium	UBERON:0002081	78.57	gold quality
left coronary artery	UBERON:0001626	77.90	gold quality
duodenum	UBERON:0002114	77.58	gold quality
coronary artery	UBERON:0001621	77.13	gold quality
heart left ventricle	UBERON:0002084	76.85	gold quality
muscle of leg	UBERON:0001383	76.79	gold quality
mouth mucosa	UBERON:0003729	76.69	gold quality
heart	UBERON:0000948	76.63	gold quality
cardiac ventricle	UBERON:0002082	76.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting KAZALD1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-2110	99.96	66.68	1930
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-323B-3P	99.14	68.89	725
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-5187-5P	98.54	67.94	952
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-3198	97.84	65.64	579
HSA-MIR-4309	97.84	65.45	588
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-509-3-5P	97.21	67.74	1517
HSA-MIR-509-5P	97.21	67.90	1512
HSA-MIR-335-5P	97.10	68.12	1022
HSA-MIR-4418	97.04	67.16	1372
HSA-MIR-1288-3P	96.86	66.95	536
HSA-MIR-6813-3P	95.78	63.78	540

Literature-anchored findings (GeneRIF, showing 6)

• Expression of Bono1 was detected in osteoblasts and secretory odontoblasts by in situ hybridization. (PMID:15261838)
• This paper describes the identification and expression pattern of the mouse ortholog of the human gene. (PMID:15261838)
• This paper suggests that the mouse ortholog of this human gene plays a role in bone formation and regeneration. (PMID:15555553)
• KAZALD1 gene was hypermethylated in sarcomatoid-type malignant peritoneal mesothelioma. (PMID:22836805)
• KAZALD1 promotes glioma malignant progression through invasion and proliferation (PMID:24002581)
• KAZALD1 hypomethylation indicates bad prognosis in small bowel adenocarcinoma (PMID:26315110)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kazald3	ENSDARG00000053509
mus_musculus	Kazald1	ENSMUSG00000025213
rattus_norvegicus	Kazald1	ENSRNOG00000016058

Paralogs (2): IGFBPL1 (ENSG00000137142), IGFBP7 (ENSG00000163453)

Protein

Protein identifiers

Kazal-type serine protease inhibitor domain-containing protein 1 — Q96I82 (reviewed: Q96I82)

All UniProt accessions (1): Q96I82

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the proliferation of osteoblasts during bone formation and bone regeneration. Promotes matrix assembly.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96I82-1	1	yes
Q96I82-2	2

RefSeq proteins (2): NP_001306232, NP_112191* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000867	IGFBP-like	Domain
IPR002350	Kazal_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011390	IGFBP_rP_mac25	Family
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF00219, PF07648, PF07679

UniProt features (22 total): disulfide bond 8, sequence variant 4, domain 3, glycosylation site 3, splice variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96I82-F1	82.85	0.62

Functional residue map

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

Disulfide bonds (8): 61–79, 67–82, 90–108, 102–126, 135–168, 193–253, 53–76, 56–78

Glycosylation sites (3): 159, 183, 277

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 152 (showing top): AHRARNT_01, BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, MYOGENIN_Q6, GCANCTGNY_MYOD_Q6, GOBP_GROWTH, CCANNAGRKGGC_UNKNOWN, MYOD_01, MODULE_99, MYOD_Q6, GOBP_OSSIFICATION, GOMF_SIGNALING_RECEPTOR_BINDING, YNGTTNNNATT_UNKNOWN, IVANOVA_HEMATOPOIESIS_STEM_CELL_LONG_TERM, GOBP_CELL_GROWTH

GO Biological Process (5): ossification (GO:0001503), regulation of cell growth (GO:0001558), regulation of signal transduction (GO:0009966), cell differentiation (GO:0030154), extracellular matrix organization (GO:0030198)

GO Molecular Function (2): insulin-like growth factor binding (GO:0005520), protein binding (GO:0005515)

GO Cellular Component (4): interstitial matrix (GO:0005614), obsolete extracellular space (GO:0005615), extracellular region (GO:0005576), extracellular matrix (GO:0031012)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
multicellular organismal process	1
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
cellular developmental process	1
extracellular structure organization	1
external encapsulating structure organization	1
growth factor binding	1
binding	1
extracellular matrix	1
cellular anatomical structure	1
external encapsulating structure	1

Protein interactions and networks

STRING

202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KAZALD1	FST	P19883	644
KAZALD1	CDC50B	Q3MIR4	581
KAZALD1	BMP2	P12643	530
KAZALD1	FBXW4	P57775	413
KAZALD1	PCSK6	P29122	410
KAZALD1	NGFR	P08138	400
KAZALD1	NTRK3	Q16288	400
KAZALD1	ITGB3	P05106	397
KAZALD1	IGFBP7	Q16270	376
KAZALD1	NPM3	O75607	349
KAZALD1	POLL	Q9UGP5	348
KAZALD1	INS	P01308	343
KAZALD1	WDR11	Q9BZH6	329
KAZALD1	RD3L	P0DJH9	307
KAZALD1	MAPK13	O15264	290

IntAct

8 interactions, top by confidence:

A	B	Type	Score
BAG6	KAZALD1	psi-mi:“MI:0915”(physical association)	0.560
KLF11	KAZALD1	psi-mi:“MI:0915”(physical association)	0.560
KAZALD1	ZNF865	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): KAZALD1 (Affinity Capture-RNA), KAZALD1 (Affinity Capture-RNA), ZNF709 (Affinity Capture-MS), ZNF146 (Affinity Capture-MS), ZNF579 (Affinity Capture-MS), ZNF865 (Affinity Capture-MS), ZNF101 (Affinity Capture-MS), ZNF444 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), ZNF627 (Affinity Capture-MS), ZNF696 (Affinity Capture-MS), KAZALD1 (Affinity Capture-RNA)

ESM2 similar proteins: A2A9Q0, A5A8Y8, A5PKD8, F1SAM7, O00468, O60500, O75325, P0C7J6, P12843, P13384, P18065, P24853, P49705, P50895, P60827, P60882, Q16270, Q24JP5, Q29400, Q2WF71, Q50LG9, Q5W7P8, Q61581, Q641Q3, Q6IQX7, Q6UKI2, Q6UWL6, Q75ZP3, Q7TSU7, Q7Z7M0, Q80W15, Q8BHA1, Q8BJ66, Q8IZ52, Q8N2S1, Q8NDA2, Q8WX77, Q91ZV8, Q96I82, Q96MS0

Diamond homologs: A0JNK3, A2RNT9, A2RT60, A4IHA1, A4XSC0, A5PKD8, A5W8F5, A6VUA4, A6YFB5, A9JRB3, B0KV30, B1J4D7, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D0ZY51, D3ZA76, D3ZKF5, E1BJW1, E1V4H2, F1N152, F6AA62, O05942, O06291, O22609, O31754, O34358, O43464, O53896, O85291, P05676, P0A3Z5, P0AEE3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

660 predictions. Top by Δscore:

Variant	Effect	Δscore
10:101063040:G:GT	donor_gain	1.0000
10:101064813:T:G	acceptor_gain	1.0000
10:101063101:CGGGT:C	donor_loss	0.9900
10:101063102:GG:G	donor_gain	0.9900
10:101063102:GGGT:G	donor_loss	0.9900
10:101063103:GG:G	donor_gain	0.9900
10:101063103:GGT:G	donor_loss	0.9900
10:101063104:G:A	donor_loss	0.9900
10:101063104:G:GG	donor_gain	0.9900
10:101063105:T:G	donor_loss	0.9900
10:101064367:G:GT	donor_gain	0.9900
10:101064807:T:TA	acceptor_gain	0.9900
10:101064812:AT:A	acceptor_gain	0.9900
10:101064812:ATGT:A	acceptor_gain	0.9900
10:101064813:T:TA	acceptor_gain	0.9900
10:101064815:T:TA	acceptor_gain	0.9900
10:101064824:A:AG	acceptor_gain	0.9900
10:101064825:G:GG	acceptor_gain	0.9900
10:101062108:GACAC:G	donor_gain	0.9800
10:101062112:CTAGG:C	donor_loss	0.9800
10:101062113:TAGGT:T	donor_loss	0.9800
10:101062114:AGGTG:A	donor_loss	0.9800
10:101062116:GTGAG:G	donor_loss	0.9800
10:101062117:T:G	donor_loss	0.9800
10:101062536:T:A	acceptor_gain	0.9800
10:101062540:AG:A	acceptor_gain	0.9800
10:101062541:GG:G	acceptor_gain	0.9800
10:101064397:G:T	donor_gain	0.9800
10:101064398:G:T	donor_gain	0.9800
10:101064812:A:AG	acceptor_gain	0.9800

AlphaMissense

1943 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:101064364:G:C	W205C	1.000
10:101064364:G:T	W205C	1.000
10:101064362:T:A	W205R	0.999
10:101064362:T:C	W205R	0.999
10:101062860:T:A	C90S	0.997
10:101062861:G:C	C90S	0.997
10:101064541:T:C	L238P	0.997
10:101064547:T:C	I240T	0.997
10:101062861:G:A	C90Y	0.996
10:101064326:T:A	C193S	0.996
10:101064327:G:A	C193Y	0.996
10:101064327:G:C	C193S	0.996
10:101064363:G:C	W205S	0.996
10:101064539:G:C	W237C	0.996
10:101064539:G:T	W237C	0.996
10:101064579:T:G	Y251D	0.996
10:101064585:T:A	C253S	0.996
10:101064586:G:C	C253S	0.996
10:101062914:T:A	C108S	0.995
10:101062915:G:C	C108S	0.995
10:101064326:T:C	C193R	0.994
10:101062861:G:T	C90F	0.993
10:101062896:T:A	C102S	0.993
10:101062897:G:A	C102Y	0.993
10:101062897:G:C	C102S	0.993
10:101062995:T:A	C135S	0.993
10:101062996:G:C	C135S	0.993
10:101064631:T:C	L268S	0.993
10:101062862:C:G	C90W	0.992
10:101062968:T:A	C126S	0.992

dbSNP variants (sampled 300 via entrez): RS1000096923 (10:101060152 C>A,G), RS1000408810 (10:101060525 A>C,G), RS1001109941 (10:101064838 C>T), RS1001456143 (10:101063234 T>C), RS1002115556 (10:101063639 G>A), RS1002655063 (10:101067616 T>C), RS1003468779 (10:101060857 C>T), RS1003673278 (10:101066167 A>G), RS1004619210 (10:101062025 C>G,T), RS1005577755 (10:101061894 C>G), RS1005633217 (10:101062177 C>G,T), RS1006033060 (10:101066549 G>A), RS1006033522 (10:101061031 G>A,C), RS1006142982 (10:101066335 G>A), RS1006534391 (10:101066150 G>A)

Disease associations

OMIM: gene MIM:609208 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005580_150	Intraocular pressure	8.000000e-09
GCST006291_24	Spherical equivalent or myopia (age of diagnosis)	5.000000e-08
GCST006921_7	Regular attendance at a pub or social club	1.000000e-08
GCST010002_298	Refractive error	3.000000e-22
GCST012400_8	Low myopia vs hyperopia	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0004847	age at onset
EFO:0009592	social interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	4
bisphenol A	affects expression, affects cotreatment, decreases methylation, increases expression	3
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Troglitazone	decreases expression	1
Air Pollutants	decreases expression	1
Arsenic	affects methylation	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	affects expression	1
Lipopolysaccharides	affects response to substance, increases expression	1
Naled	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Progesterone	decreases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1

Clinical trials (associated diseases)

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