Alternative titles; symbols
HGNC Approved Gene Symbol: ITIH4
Cytogenetic location: 3p21.1 Genomic coordinates (GRCh38): 3:52,812,962-52,830,672 (from NCBI)
The inter-alpha-trypsin inhibitors (ITI) are a family of structurally related plasma serine protease inhibitors involved in extracellular matrix stabilization and in prevention of tumor metastasis. The ITI family contains multiple proteins made up of a light chain (see 176870) and a variable number of heavy chains (Salier et al., 1987; Himmelfarb et al., 2004).
Nishimura et al. (1995) identified a 120-kD kallikrein-3 (KLK3; 176820)-sensitive glycoprotein (ITIH4) from human plasma. The glycoprotein, designated PK120 by them, circulates in the plasma at a concentration of 80 micrograms per milliliter and is cleaved by KLK3 into smaller fragments. The authors obtained partial amino acid sequence of purified PK120 from which degenerate PCR primers were designed. They obtained an RT-PCR product from human liver poly(A)+ RNA and used it to screen a human liver cDNA library. Their PK120 cDNA of 3,058 bp codes for a putative 28-amino acid signal sequence followed by a mature protein of 902 residues, 211 of which were confirmed by protein sequencing. Northern blots identified a strong 3.3-kb and a fainter 4-kb transcript in liver. The sequence shared similarity to the inter-alpha-trypsin inhibitor (ITI) superfamily.
Saguchi et al. (1995) reported the sequence of a cDNA for a glycoprotein found in plasma that they designated 'inter-alpha-trypsin inhibitor family heavy chain-related protein' (IHRP). Based on partial amino acid sequence, the authors designed PCR primers, which were used to screen liver cDNA. The products were then used to screen liver cDNA libraries. The complete IHRP cDNA encodes a 930-residue protein. The N-terminal 28 amino acids corresponded to a signal peptide required for secretion. The first two-thirds of the predicted protein showed significant sequence similarity to the ITI heavy chains H1 (ITIH1; 147270) (52%), H2 (ITIH2; 146640) (49%), and H3 (ITIH3; 146650) (57%). Northern blot analysis demonstrated IHRP expression only in liver.
Nishimura et al. (1995) speculated that the products of PK120 proteolysis may bind to hyaluronic acid, a major component of the extracellular matrix.
Tobe et al. (1995) reported fluorescence in situ hybridization studies using a 2.5-kb cDNA fragment as a probe and indicating that the ITIHL1 gene is located in chromosome region 3p21-p14, where the ITIH1 and ITIH3 genes are located. This result, together with significant homology between the nucleotide sequences of ITIHL1 and the other 2 genes, supports the conclusion that ITIHL1 is a member of an evolutionarily related gene family of ITI heavy chains.
Jean et al. (1997) mapped the human ITIH4 gene to 3p21.2-p14.1 by in situ hybridization. They mapped the mouse Itih4 gene to chromosome 14 by interspecific backcross analysis. In both human and mouse, the ITIH4 gene maps near the ITIH1 and ITIH3 genes. Diarra-Mehrpour et al. (1998) reported that the 3 ITIH genes are arranged ITIH1--ITIH3--ITIH4 in a cluster that spans 45 kb. The ITIH4 gene is transcribed in the opposite orientation from the others.
This variant, formerly titled HYPERCHOLESTEROLEMIA, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by Hamosh (2019).
Fujita et al. (2004) reported an association between a C/T single nucleotide polymorphism (SNP) at position +8 in intron 17 of the ITIH4 gene and plasma total cholesterol levels in 351 adult individuals from an east-central area of Japan. Those who lacked the T allele had significantly higher plasma total cholesterol levels than the others who had the T allele. Of the 309 without the T allele, approximately 90% presented with hypercholesterolemia (see 143890), whereas only 10% were hypercholesterolemic among 42 individuals with the T allele. They interpreted the data as suggesting that genetic variation at the ITIH4 locus is a determinant of plasma cholesterol metabolism.
Hamosh (2019) found that this variant was present in heterozygous state in 82,160 of 282,140 alleles and in 13,332 homozygotes, at an allele frequency of 0.2912, in the gnomAD database (June 19, 2019).
Diarra-Mehrpour, M., Sarafan, N., Bourguignon, J., Bonnet, F., Bost, F., Martin, J.-P. Human inter-alpha-trypsin inhibitor heavy chain H3 gene: genomic organization, promoter analysis, and gene linkage. J. Biol. Chem. 273: 26809-26819, 1998. Note: Erratum: J. Biol. Chem. 273: 30842 only, 1988. [PubMed: 9756925] [Full Text: https://doi.org/10.1074/jbc.273.41.26809]
Fujita, Y., Ezura, Y., Emi, M., Sato, K., Takada, D., Iino, Y., Katayama, Y., Takahashi, K., Kamimura, K., Bujo, H., Saito, Y. Hypercholesterolemia associated with splice-junction variation of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) gene. J. Hum. Genet. 49: 24-28, 2004. [PubMed: 14661079] [Full Text: https://doi.org/10.1007/s10038-003-0101-8]
Hamosh, A. Personal Communication. Baltimore, Md. 6/19/2019.
Himmelfarb, M., Klopocki, E., Grube, S., Staub, E., Klaman, I., Hinzmann, B., Kristiansen, G., Rosenthal, A., Durst, M., Dahl, E. ITIH5, a novel member of the inter-alpha-trypsin inhibitor heavy chain family is downregulated in breast cancer. Cancer Lett. 204: 69-77, 2004. [PubMed: 14744536] [Full Text: https://doi.org/10.1016/j.canlet.2003.09.011]
Jean, L., Smih, F., Olivier, E., Soury, E., Simon-Chazottes, D., Guenet, J. L., Mattei, M. G., Salier, J. P. Comparative assignments of the genes of the inter-alpha-inhibitor family in human and mouse: ITIH4 is close to ITIH1 and ITIH3, on HSA 3 and MMU 14. Genomics 41: 139-140, 1997. [PubMed: 9126497] [Full Text: https://doi.org/10.1006/geno.1997.4612]
Nishimura, H., Kakizaki, I., Muta, T., Sasaki, N., Pu, P. X., Yamashita, T., Nagasawa, S. cDNA and deduced amino acid sequence of human PK-120, a plasma kallikrein-sensitive glycoprotein. FEBS Lett. 357: 207-211, 1995. [PubMed: 7805892] [Full Text: https://doi.org/10.1016/0014-5793(94)01364-7]
Saguchi, K., Tobe, T., Hashimoto, K., Sano, Y., Nakano, Y., Miura, N.-H., Tomita, M. Cloning and characterization of cDNA for inter-alpha-trypsin inhibitor family heavy chain-related protein (IHRP), a novel human plasma glycoprotein. J. Biochem. 117: 14-18, 1995. [PubMed: 7775381] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a124701]
Salier, J. P., Diarra-Mehrpour, M., Sesboue, R., Bourguignon, J., Benarous, R., Ohkubo, I., Kurachi, S., Kurachi, K., Martin, J. P. Isolation and characterization of cDNAs encoding the heavy chain of human inter-alpha-trypsin inhibitor (IATI): unambiguous evidence for multipolypeptide chain structure of IATI. Proc. Nat. Acad. Sci. 84: 8272-8276, 1987. [PubMed: 2446322] [Full Text: https://doi.org/10.1073/pnas.84.23.8272]
Tobe, T., Saguchi, K., Hashimoto, K., Miura, N.-H., Tomita, M., Li, F., Wang, Y., Minoshima, S., Shimizu, N. Mapping of human inter-alpha-trypsin inhibitor family heavy chain-related protein gene (ITIHL1) to human chromosome 3p21-p14. Cytogenet. Cell. Genet. 71: 296-298, 1995. [PubMed: 7587397] [Full Text: https://doi.org/10.1159/000134130]