Deepak C, Ramanathan A. Role of ARHGAP29 Gene in Orofacial Clefting : A Systematic Review. Biomed Pharmacol J 2017;10(3).
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Manuscript accepted on :July 18, 2017
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C. Deepakand Arvind Ramanathan2

1Department of Orthodontics, Bharath University Chennai, India.

2Sree Balaji Dental College and Hospital Bharath University Chennai, India.

Corresponding Author E-mail: drcdeepak1307@gmail.com

DOI : https://dx.doi.org/10.13005/bpj/1211

Abstract

The Gene ARHGAP 29, has long been considered as a candidate gene for Orofacial clefting . There has been considerable interest in finding the human studies that are involved in ARHGAP 29 gene. A need for a systematic review of literature was felt. The search bases Pubmeb , Cochrane and science direct were chosen and with the inclusion criteria of the study , three studies were shortlisted. The studies found a link between the ARHGAP29 gene and Orofacial clefting.

Keywords

ARHGAP29 gene; systematic review; orofacial clefting

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Deepak C, Ramanathan A. Role of ARHGAP29 Gene in Orofacial Clefting : A Systematic Review. Biomed Pharmacol J 2017;10(3).

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Deepak C, Ramanathan A. Role of ARHGAP29 Gene in Orofacial Clefting : A Systematic Review. Biomed Pharmacol J 2017;10(3). Available from: http://biomedpharmajournal.org/?p=15839

Introduction

Orofacial clefting has since time immemorial affected humans  . It affects the  individual in many ways ,which includes the  phycological and  physical aspects  . The Incidence of orofacial clefts in India has been reported to be around 1:500.2 Orofacial clefts range  from an isolated cleft around the face to a bilateral cleft lip and palate of the affected individual. The severe facial deformation associated with the clefting ,renders the affected individuals with  a psychological set back. Some developing and underdeveloped  countries suffer from a deficiency of sufficient health care for the patients with clefting. In countries like  India where the cleft care does not reach the rural population , the severity of the psychological and physical effects can be felt  .
The search for eitiology of orofacial clefting has been a topic of contemporary  research for quite sometime  now. While the two forms of orofacial clefting, the syndromic and non syndromic clefting have been under research for a while now  . The interest generated in  non syndromic clefting has increased relatively more, as it involves an  apparently healthy individual  with orofacial clefting and without any other systemic condition.

In  1969 Carter proposed a model (MF/T) 1 multifactorial clefting  inheritance, where he stated that non syndromic clefting was caused by the additive effects of minor abnormal genes and environmental factors.

ARHGAP29 Gene

ARHGAP29  gene is  found  on the  chromosome 1p22 that  forms the  Rho GTPase activating protein (GAP) 29,3 this protein mediates the cyclical regulation of smaller GTP( binding) proteins such as RhoA.4

Function

The gene ARHGAP29 is found in the developing face and may also act downstream of IRF6  gene in craniofacial development3

Structure

The Gene ARHGAP29 contains a total of four domains including a coiled-coil region, this is  known to interact with the  Rap2,6 the  C1 domain, GTPase domain, the Rho, and a small C-terminal region that interacts with PTPL1.4

Clinical Significance

The 1p22 locus having the  ARHGAP29 was long associated with nonsydromic cleft lip/palate clefting a by genome wide association7 and meta-analysis.8 A follow-up study5 identified rare coding variants that  included  a nonsense and subsequently a  frameshift variant in patients with nonsydromic cleft lip/palate. The gene  ARHGAP29’s primary  role in craniofacial development was found  after an  adjacent ABCA4 gene lacked functional or expression data to support it as the main  etiologic gene  responsible for nonsydromic cleft lip/palate,  even though earlier the  SNPs in the ABCA4 gene were associated with  nonsyndromic  cleft lip/palate.

To test the Null Hypothesis

The ARHGAP 29 gene  mutation is responsible for  orofacial clefting.

Methodology

Three search bases , Pubmed , Science direct and Cochrane were searched using the key words.

The Inclusion criteria used in the study was:

A Direct association of the ARHGAP29 gene mutation to orofacial clefting
Human subjects with Cleft

Results

Pub med direct gave 22, Science direct 6 and Cochrane 0 articles.

Further  using the inclusion criteria, 3 articles were selected

Discussion

The Role of ARHGap 29  gene  in Human orofacial clefting has  been a topic of debate for sometime now, the  present systematic review was designed to research  if there were any human studies that implicated orofacial clefting to the ARHGAP29  gene . In all the  3 studies have implicated a direct relation to orofacial clefting . These studies have covered a broad research database spanning three major databases . Venkatesh Babu Gurramkonda et all9 in a sample of 173 cases and 176 controls of nonsyndromic cleft lip and palate patients, could not find single nucleotide polymorphisms (SNP)  located at chromosomal region 1p22, further the authors concluded that there was no link to south Indian non syndromic cleft lip & palate. Elizebeth J Leslie et all10 in a study done on 182 individuals from the US and Phillipines affected with Nonsyndromic cleft lip & palate found that the gene  ARHGAP29 revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant. Deepak Chandrasekharan and Arvind ramanathan11 reported a nonsense mutation in exon 1 of ARHGAP29 that caused substitution of lysine to stop codon at codon position 32 in a subject with nonsyndromic cleft lip with cleft palate among 60 patient samples. The reports of ARHGAP 29 gene in orofacial clefting is rare but has been reported from populations around the world.

Conclusion

The ARHGAP 29 gene,  has been implicated in the formation of orofacial clefting. Several human studies have shown mutations in different populations.

Conflict of Interest

The Authors would like to thank Bharath University for providing the facility for the study.

There is no conflict of Interest.

References

  1. Carter C. O.  Genetics of Common Disorders. Br.Med. Bul. 1969;25:52.
    CrossRef
  2.  Prasad S. V., Shivani V. Genetic significance of muscle segment homeo box1 gene in South Indian population for cleft lip and palate. Indian Journal of Human genetics. 2012;18(3):332-339.
    CrossRef
  3. Heasman S. J., Ridle  A. J. Mammalian Rho GT Pases new insights into their functions from in vivo studies.Nat Rev Mol Cell Biol. 2008;(9):690–701.
    CrossRef
  4. Saras J., Franzen P., Aspenstrom P., Hellman U., Gonez L. J., Heldin C. H . A novel GTPase-activating protein for Rho interacts with a PDZ domain of the protein-tyrosine phosphatase PTPL 1. J Biol Chem. 1997;272(39):24333–24338.
    CrossRef
  5. Leslie E. J., Mansilla M. A., Biggs L. C., Schuette K., Bullard S., Cooper M., Dunnwald M., Lidral A.C., Marazita M. L., Beaty T. H., Murray J. C. Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome-wide association on chromosome 1p22, Birth Defects Research Part A: Clinical and Molecular Teratology. 2012;94:934–942.
    CrossRef
  6. Myagmar B. E., Umikawa M., Asato T., Taira K., Oshiro M., Hino A., Takei K., Uezato H., Kariya K. PARG1, a protein-tyrosine phosphatase-associated RhoGAP, as a putative Rap2 effector. Biochem Biophys Res Commun. 2005;329(3):1046–1052.
    CrossRef
  7. Beaty T. H., Murray J. C., Marazita M. L., Munger R. G., Ruczinski I., Hetmanski J. B., Liang K. Y., Wu T., Murray T., Fallin M. D., Redett R. A., Raymond G., Schwender H., Jin S.C., Cooper M. E., Dunnwald M., Mansilla M. A., Leslie E., Bullard S., Lidral A. C., Moreno L. M., Menezes R., Vieira A.R., Petrin A., Wilcox A. J., Lie R. T., Jabs E. W., Wu-Chou Y. H., Chen P. K., Wang H., Ye X., Huang S., Yeow V., Chong S. S., Jee S. H., Shi B., Christensen K., Melbye M., Doheny K. F., Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F., Mills J. L., Molloy A. M., Kirke P. N., Scott J. M., Arcos-Burgos M., Scott A. F .A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nature Genetics. 2010;42(6):525–529.
    CrossRef
  8. Ludwig K. U., Mangold E., Herms S., Nowak S., Reutter H., Paul A., Becker J., Herberz R., AlChawa T., Nasser E., Böhmer A. C., Mattheisen M., Alblas M. A., Barth S., Kluck N., Lauster C., Braumann B., Reich R. H., Hemprich A., Pötzsch S., Blaumeiser B., Daratsianos N., Kreusch T., Murray J. C., Marazita M. L., Ruczinski I., Scott A. F., Beaty T.H., Kramer F. J., Wienker T. F., Steegers-Theunissen R. P., Rubini M., Mossey P. A., Hoffmann P., Lange C., Cichon S., Propping P., Knapp M., Nöthen M. M. Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk lociNature Genetics. 2012;44(9):968–971.
    CrossRef
  9.  Konda V. B. G., Syed A. H., Murthy J., Chaubey G.,Lakkakula V. K. S. B. Polymorphic variants near 1p22 and 20q11.2 loci and the risk of non-syndromic cleft lip and palate in South Indian population. Int . journal of Pediatric Otorhinolaryngology. 2015;79(12):2389-2393.
    CrossRef
  10. Leslie J. E.,  Mansilla M. A.,  Biggs C. L.,  Schuette K., Bullard S.,Cooper, Martine Dunnwald M.,  Lidral C. A.,Marazita L. M., Beaty T. H and Murray C. J. Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome wide association on chromosome 1p 22. Birth Defects Res A Clin Mol Teratol. 2012;94(11):934-942.
    CrossRef
  11.  Chandrasekharan D and Ramanathan A. Identification of a novel heterozygous truncation mutation in exon 1 of ARHGAP29 in an Indian subject with nonsyndromic cleft lip with cleft palate. Eur J Dent. 2014;8(4):528–532.
    CrossRef
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