Chordin-like 1 explained

Chordin-like 1 is a protein that in humans is encoded by the CHRDL1 gene.^[1] Chordin-Like 1 (CHRDL1) is a structural glycoprotein that sits on the X chromosome and specifically encodes Venotropin, which is an antagonistic protein to bone morphogenic protein 4.^[2]

Function

This gene encodes an antagonist of bone morphogenetic protein 4. The encoded protein may play a role in topographic retinotectal projection and in the regulation of retinal angiogenesis in response to hypoxia. Alternatively spliced transcript variants encoding different isoforms have been described.^[1]

CHRDL1 plays important roles in processes such as embryonic cell differentiation, osteogenesis, neurogenesis, tumor and metastasis suppression, and retinal formation.^{[3] [4]} The highest expression of this gene is found in the anterior eye segment and retina as well as in the cerebellum and neocortex. In the neocortex, it peaks at the time of synapse maturation to allow for proper synaptic formation.^[5] Therefore, this gene is important in proper formation of the central nervous system and the eyes.

Clinical significance

Mutations in CHRDL1 are associated to Neuhäuser Syndrome, X-linked megalocornea and central corneal thickness.^[6]

Mutations in this gene may cause a variety of effects on the aforementioned processes. One potential outcome of a CHRDL1 mutation is non-syndromic X-linked megalocornea (XMC) that results from either a missense, nonsense, or frameshift mutation of the gene. XMC is an enlargement of the anterior segments of the eye that may lead to other issues such as cataracts and glaucoma. Another potential outcome is carcinogenic formation. Since CHRDL1 is a tumor and metastasis suppressor, a mutation in this gene may lead to tumor cell formation. The most major effect a mutation could have is on synaptic stabilization. Since the gene limits synaptic plasticity, a mutation may cause issues in proper synapse maturation, leading to a variety of neurological disorders. There is currently a knockout model for this gene that shows disruption may cause altered synaptic events and reduced synaptic GluA2 AMPARs leading to reduced plasticity.

Further reading

• Sakuta H, Suzuki R, Takahashi H, Kato A, Shintani T, Yamamoto TS, Ueno N, Noda M . 6 . Ventroptin: a BMP-4 antagonist expressed in a double-gradient pattern in the retina . Science . 293 . 5527 . 111–5 . July 2001 . 11441185 . 10.1126/science.1058379 . 32368073 .
• Webb TR, Matarin M, Gardner JC, Kelberman D, Hassan H, Ang W, Michaelides M, Ruddle JB, Pennell CE, Yazar S, Khor CC, Aung T, Yogarajah M, Robson AG, Holder GE, Cheetham ME, Traboulsi EI, Moore AT, Sowden JC, Sisodiya SM, Mackey DA, Tuft SJ, Hardcastle AJ . 6 . X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development . American Journal of Human Genetics . 90 . 2 . 247–59 . February 2012 . 22284829 . 3276677 . 10.1016/j.ajhg.2011.12.019 .
• Kane R, Godson C, O'Brien C . Chordin-like 1, a bone morphogenetic protein-4 antagonist, is upregulated by hypoxia in human retinal pericytes and plays a role in regulating angiogenesis . Molecular Vision . 14 . 1138–48 . June 2008 . 18587495 . 2435163 .
• Fernandes H, Dechering K, van Someren E, Steeghs I, Apotheker M, Mentink A, van Blitterswijk C, de Boer J . 6 . Effect of chordin-like 1 on MC3T3-E1 and human mesenchymal stem cells . Cells Tissues Organs . 191 . 6 . 443–52 . 2010 . 20130390 . 10.1159/000281825 . 39732221 .
• A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease . Nature Genetics . 43 . 4 . 339–44 . March 2011 . 21378988 . 10.1038/ng.782 . Coronary Artery Disease (C4D) Genetics Consortium . 39712343 .
• Larman BW, Karolak MJ, Adams DC, Oxburgh L . Chordin-like 1 and twisted gastrulation 1 regulate BMP signaling following kidney injury . Journal of the American Society of Nephrology . 20 . 5 . 1020–31 . May 2009 . 19357253 . 2678041 . 10.1681/ASN.2008070768 .
• Coffinier C, Tran U, Larraín J, De Robertis EM . Neuralin-1 is a novel Chordin-related molecule expressed in the mouse neural plate . Mechanisms of Development . 100 . 1 . 119–22 . January 2001 . 11118896 . 10.1016/s0925-4773(00)00507-4 .
• Gazzerro E, Canalis E . Bone morphogenetic proteins and their antagonists . Reviews in Endocrine & Metabolic Disorders . 7 . 1–2 . 51–65 . June 2006 . 17029022 . 10.1007/s11154-006-9000-6 . 20907947 .
• Chen D, Zhao M, Mundy GR . Bone morphogenetic proteins . Growth Factors . 22 . 4 . 233–41 . December 2004 . 15621726 . 10.1080/08977190412331279890 . 22932278 .

Notes and References

1. Web site: Entrez Gene: Chordin-like 1 . 2014-08-06 .
2. Pfirrmann T, Emmerich D, Ruokonen P, Quandt D, Buchen R, Fischer-Zirnsak B, Hecht J, Krawitz P, Meyer P, Klopocki E, Stricker S, Lausch E, Seliger B, Hollemann T, Reinhard T, Auw-Haedrich C, Zabel B, Hoffmann K, Villavicencio-Lorini P . 6 . Molecular mechanism of CHRDL1-mediated X-linked megalocornea in humans and in Xenopus model . Human Molecular Genetics . 24 . 11 . 3119–32 . June 2015 . 25712132 . 10.1093/hmg/ddv063 . free .
3. Liu T, Li B, Zheng XF, Jiang SD, Zhou ZZ, Xu WN, Zheng HL, Wang CD, Zhang XL, Jiang LS . 6 . Chordin-Like 1 Improves Osteogenesis of Bone Marrow Mesenchymal Stem Cells Through Enhancing BMP4-SMAD Pathway . en . Frontiers in Endocrinology . 10 . 360 . 2019 . 31249554 . 10.3389/fendo.2019.00360 . 6582276 . free .
4. Pei YF, Zhang YJ, Lei Y, Wu WD, Ma TH, Liu XQ . Hypermethylation of the CHRDL1 promoter induces proliferation and metastasis by activating Akt and Erk in gastric cancer . Oncotarget . 8 . 14 . 23155–23166 . April 2017 . 28423564 . 10.18632/oncotarget.15513 . 5410293 .
5. Blanco-Suarez E, Liu TF, Kopelevich A, Allen NJ . Astrocyte-Secreted Chordin-like 1 Drives Synapse Maturation and Limits Plasticity by Increasing Synaptic GluA2 AMPA Receptors . Neuron . 100 . 5 . 1116–1132.e13 . December 2018 . 30344043 . 6382071 . 10.1016/j.neuron.2018.09.043 .
6. Davidson AE, Cheong SS, Hysi PG, Venturini C, Plagnol V, Ruddle JB, Ali H, Carnt N, Gardner JC, Hassan H, Gade E, Kearns L, Jelsig AM, Restori M, Webb TR, Laws D, Cosgrove M, Hertz JM, Russell-Eggitt I, Pilz DT, Hammond CJ, Tuft SJ, Hardcastle AJ . 6 . Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness . PLOS ONE . 9 . 8 . e104163 . 2014 . 25093588 . 4122416 . 10.1371/journal.pone.0104163 . 2014PLoSO...9j4163D . free .