The COCH (Coagulation factor C homology) gene, located in human chromosome 14q12-q13, is the first gene identified to cause vestibular dysfunction. COCH encodes cochlin, which contains an N-terminal LCCL (Limulus factor C, cochlin, and late gestation lung protein Lgl1) domain and a C-temimal vWFA (Von Willebrand factor type A) domain. Recently, functional research of COCH mutations and cochlin have come under the spotlight in the field of hereditary deafness. Approximately 16 mutations in COCH have been confirmed to date, among which 13 non-synonymous single nucleotide polymorphisms (nsSNPs) are the most common form of genetic variations. Nonetheless, there is poor knowledge on the relationship between the genotype and the phenotype of the other nsSNPs in COCH. Here we analyzed deleterious nsSNPs from all SNPs in the COCH gene in the vWFA domain based on different computational methods and identified eight potential pathogenic nsSNPs (I176T, R180Q, G265E, V269L, I368N, I372T, R416C and Y424D) after combining literatures with 3D structures. Meanwhile, the protein structures of six reported pathogenic nsSNPs (P51S, G87W, I109N, I109T, W117R and F121S) in the LCCL domain have been constructed, and we identified aberrant structural changes in loops and chains. The prediction of pathogenic mutations for COCH nsSNPs will provide a blueprint for screening pathogenic mutations, and it will be beneficial to the functional research of COCH and cochlin in this field.
[1] Looi LM, Ganten D, McGrath PF, Gross M, Griffin GE. Hearing loss: a global health issue. Lancet , 2015, 385(9972): 943-944.
[2] Cohen MM, Gorlin RJ. Epidemiology, etiology and genetic patterns. In: Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and Its Syndromes. New York: Oxford University Press, 1995: 457.
[3] Tekin M, Arnos KS, Pandya A. Advances in hereditary deafness. Lancet , 2001, 358(9287): 1082-1090.
[4] Simon A, Xi L, Xue ZL. Genetics of Hearing and Deafness. Anat Rec , 2012, 295(11): 1812-1829.
[5] Van Camp G, Smith R. Hereditary hearing loss homepage. http: //hereditaryhearingloss.org/.
[6] Fransen E, Van Camp G. The COCH gene: a frequent cause of hearing impairment and vestibular dysfunction? Br J Audio , 1999, 33(5): 297-302.
[7] Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC. Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening. Genomics , 1994, 23(1): 42-50.
[8] Kamaraj B, Purohit R. In silico screening and molecular dynamics simulation of disease-associated nsSNP in TYRP1 gene and its structural consequences in OCA3. BioMed Res Int , 2013, 2013: 697051.
[9] Kumar A, Rajendran V, Sethumadhavan R, Purohit R. Computational investigation of cancer-associated molecular mechanism in Aurora A (S155R) mutation. Cell Biochem Biophys , 2013, 66(3): 787-796.
[10] Wang LL, Li Y, Zhou SF. Prediction of deleterious non-synonymous single nucleotide polymorphisms of genes related to ethanol-induced toxicity. Toxicol Letter , 2009, 187(2): 99-114.
[11] Kumar A, Purohit R. Computational investigation of pathogenic nsSNPs in CEP63 protein. Gene , 2012, 503(1): 75-82.
[12] Carvalho MA, Marsillac SM, Karchin R, Manoukian S, Grist S, Swaby RF, Urmenyi TP, Rondinelli E, Silva R, Gayol L, Baumbach L, Sutphen R, Pickard-Brzosowicz JL, Nathanson KL, Sali A, Goldgar D, Couch FJ, Radice P, Monteiro ANA. Determination of cancer risk associated with germ line brca1 missense variants by functional analysis. Cancer Res , 2007, 67(4): 1494-1501.
[13] Goldgar DF, Easton DF, Deffenbaugh AM, Monteiro ANA, Tavtigian SV, Couch FJ, Breast Cancer Information Core (BIC) Steering Committee. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to Brca1 and Brca2 . Am J Hum Genet , 2004, 75(4): 535-544.
[14] Karchin R. Next generation tools for the annotation of human SNPs. Brief Bioinform , 2009, 10(1): 35-52.
[15] Wang LL, Yang AK, Li Y, Liu JP, Zhou SF. Phenotype prediction of deleterious nonsynonymous single nucleotide polymorphisms in human alcohol metabolism-related genes: a bioinformatics study. Alcohol , 2010, 44(5): 425-438.
[16] Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K. dbSNP: The NCBI database of genetic variation. Nucleic Acids Res , 2001, 29(1): 308-311.
[17] Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN. The human gene mutation database: Building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet , 2014, 133(1): 1-9.
[18] Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. Sift web server: Predicting effects of amino acid substitutions on proteins. Nucleic Acids Res , 2012, 40(Web Server issue): W452-W457.
[19] Ng PC, Henikoff S. Sift: Predicting amino acid changes that affect protein function. Nucleic Acids Res , 2003, 31(13): 3812-3814.
[20] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods , 2010, 7(4): 248-249.
[21] Capriotti E, Fariselli P, Calabrese R, Casadio R. Predicting protein stability changes from sequences using support vector machines. Bioinformatics , 2005, 21(Suppl. 2): ii54-ii58.
[22] Capriotti E, Calabrese R, Casa
