HHIPL1

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HHIPL1
Identifiers
AliasesHHIPL1, KIAA1822, UNQ9245, HHIP like 1
External IDsMGI: 1919265 HomoloGene: 81985 GeneCards: HHIPL1
Orthologs
SpeciesHumanMouse
Entrez

84439

214305

Ensembl

ENSG00000182218

ENSMUSG00000021260

UniProt

Q96JK4

Q14DK5

RefSeq (mRNA)

NM_001127258
NM_032425
NM_001329411

NM_001044380

RefSeq (protein)

NP_001120730
NP_001316340
NP_115801

NP_001037845

Location (UCSC)Chr 14: 99.65 – 99.68 MbChr 12: 108.27 – 108.3 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

HHIP-like protein 1 (HHIPL1), also known as HHIP2, is a protein that in humans is encoded by the HHIPL1 gene on chromosome 14.[5] It is not significantly expressed in many tissues and cell types,[6] though HHIPL1 mRNA has been detected in trabecular bone cells.[7] Little is known about the precise biological function of HHIPL1, but the protein has been linked to adenomas.[8] The HHIPL1 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[9]

Structure

Gene

The HHIPL1 gene resides on chromosome 14 at the band 14q32 and contains 13 exons.[5] This gene produces 2 isoforms through alternative splicing.[10]

Protein

This protein belongs to the HHIP family and is one of three members found in humans.[10] HHIPL1 contains a SRCR domain and an N-terminal signal peptide.[7][10] Processing of the signal peptide leads to this protein's secretion. As an HHIP member, it also contains a conserved HHIP-homologous (HIPH) domain composed of 18 cysteine residues.[7]

Function

The function of HHIPL1 is not known. The section below refers to the function of HHIP.

The function of HHIP is not well known but has been shown to be tightly associated with lung function. Knocking out HHIP in mice is neonatally lethal due to defective branching in the lung.[11][12] The heterozygous knockout of HHIP has been shown to contribute to more severe emphysema induced by cigarette smoke compared to wild type mice.[13] Furthermore, increased spontaneous emphysema and oxidative stress levels have been found in the lungs of HHIP heterozygous mice.[14] Both the expression level and enhancer activity of HHIP is reduced in chronic obstructive pulmonary disease (COPD) lungs, suggesting a protective role of HHIP in COPD pathogenesis.[15]

Clinical significance

DNA methylation is one of several epigenetic modifications recognized as hallmarks of tumorigenesis. In a genome-wide survey of subtype-specific epigenomic changes in adenoma, the HHIPL1 gene was hypermethylated in 12 of 13 non-functioning (NF) adenomas, as well as in growth hormone (GH)- and prolectin-secreting adenomas. Thus, HHIPL1 has the potential to serve as a biomarker to predict or characterise tumorous growth patterns.[8] Unlike another member of the human HHIP gene family, HHIP, which is regarded as a pharmacogenomics target in the fields of oncology and vascular medicine, HHIPL1 has yet been reported with such potential.[7]

Additionally, in the cardiovascular field, HHIPL1 has been associated with CAD in Europeans, South Asians, and a population of Japanese.[16][17] However, in another study based on a Japanese population, the association failed to be replicated, suggesting that this association is population-specific.[18]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the HHIFL1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[9]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000182218 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021260 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "HHIPL1 HHIP like 1 [Homo sapiens] - Gene". National Center for Biotechnology Information (NCBI). Retrieved 2016-10-06.
  6. ^ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-06.
  7. ^ a b c d Katoh Y, Katoh M (February 2006). "Comparative genomics on HHIP family orthologs". International Journal of Molecular Medicine. 17 (2): 391–5. doi:10.3892/ijmm.17.2.391. PMID 16391842.
  8. ^ a b Duong CV, Emes RD, Wessely F, Yacqub-Usman K, Clayton RN, Farrell WE (December 2012). "Quantitative, genome-wide analysis of the DNA methylome in sporadic pituitary adenomas". Endocrine-Related Cancer. 19 (6): 805–16. doi:10.1530/ERC-12-0251. PMID 23045325.
  9. ^ a b Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, et al. (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC 4608367. PMID 25748612.
  10. ^ a b c "HHIPL1 - HHIP-like protein 1 precursor - Homo sapiens (Human) - HHIPL1 gene & protein". UniProt. Retrieved 2016-10-06.
  11. ^ Chuang PT, Kawcak T, McMahon AP (February 2003). "Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung". Genes & Development. 17 (3): 342–7. doi:10.1101/gad.1026303. PMC 195990. PMID 12569124.
  12. ^ Chuang PT, McMahon AP (February 1999). "Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein". Nature. 397 (6720): 617–21. Bibcode:1999Natur.397..617C. doi:10.1038/17611. PMID 10050855. S2CID 204991314.
  13. ^ Lao T, Glass K, Qiu W, Polverino F, Gupta K, Morrow J, et al. (2015-01-01). "Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring". Genome Medicine. 7 (1): 12. doi:10.1186/s13073-015-0137-3 (inactive 2024-03-31). PMC 4355149. PMID 25763110.{{cite journal}}: CS1 maint: DOI inactive as of March 2024 (link)
  14. ^ Lao T, Jiang Z, Yun J, Qiu W, Guo F, Huang C, et al. (August 2016). "Hhip haploinsufficiency sensitizes mice to age-related emphysema". Proceedings of the National Academy of Sciences of the United States of America. 113 (32): E4681-7. Bibcode:2016PNAS..113E4681L. doi:10.1073/pnas.1602342113. PMC 4987811. PMID 27444019.
  15. ^ Zhou X, Baron RM, Hardin M, Cho MH, Zielinski J, Hawrylkiewicz I, et al. (March 2012). "Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP". Human Molecular Genetics. 21 (6): 1325–35. doi:10.1093/hmg/ddr569. PMC 3284120. PMID 22140090.
  16. ^ Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, et al. (April 2011). "Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease". Nature Genetics. 43 (4): 333–8. doi:10.1038/ng.784. PMC 3119261. PMID 21378990.
  17. ^ Peden JF (April 2011). "A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease". Nature Genetics. 43 (4): 339–44. doi:10.1038/ng.782. PMID 21378988. S2CID 39712343.
  18. ^ Dechamethakun S, Ikeda S, Arai T, Sato N, Sawabe M, Muramatsu M (2014-01-01). "Associations between the CDKN2A/B, ADTRP and PDGFD polymorphisms and the development of coronary atherosclerosis in Japanese patients". Journal of Atherosclerosis and Thrombosis. 21 (7): 680–90. doi:10.5551/jat.22640. PMID 24573017.
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