Deepak C. Ramanathan A. Role of MSX1 Gene in Orofacial Clefting: A Systematic Review. Biomed Pharmacol J 2017;10(3).
Manuscript received on :June 08, 2017
Manuscript accepted on :June 14, 2017
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Role of MSX1 Gene in Orofacial Clefting : A Systematic Review

C. Deepak1 and Arvind Ramanathan2

1Department of Orthodonics, Bharath University Chennai, India.

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



MSX1 gene is among the Homeo box genes . The Master genes that control the downstream genes and are involved in the patterning of the face . MSX 1 deficient  mice have shown to have cleft palate and missing teeth . Several studies have been done , which have shown a  relationship between non syndromic cleft lip and palate and the MSX1 gene .  As Human studies on MSX1 and non syndromic clp are rare , this systematic review was done to see if there were sufficient literature to support the same . Three search data bases were taken , , Pubmed , Science direct and Cochrane were searched using the key words .  Pub med showed 5  , Science direct 79 and Cochrane 1 articles. Further  using the inclusion criteria , 5 articles were selected . Human studies involved populations from across the world .


MSX1 gene; systematic review; Non Syndromic cleft lip and palate

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Orofacial clefting has always been the bane of the human race. It affects the overall wellbeing of the affected individual both phycological as well as physical. The Incidence of orofacial clefts have been around 1:5004. Orofacial clefts can occur from an isolated cleft palate to a bilateral cleft lip and palate. Severe facial deformation gives the affected individuals a psychological set back. In developing countries like India where the cleft care does not reach to the rural population, the severity of unoperated clefting becomes more evident.
The search for cause of orofacial clefting has been under research for a while now . While two forms of orofacial clefting , syndromic and non syndromic clefting have been researched extensively . The interest in Non syndromic clefting has grown more as it is a condition where an apparently healthy individual  shows orofacial clefting without any other systemic condition.

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

MSX Ggenes

The MSX group of genes in vertebrates comprise of a small family of chromosomally unlinked homeobox genes related to the Drosophilia muscle segment homeobox (MSH). MSX genes are expressed in vertebrate specific  tissues , including sensory placodes , neural crest , bone and teeth. The MSX genes are classified into MSX1 and MSX2. MSX 3 found in mice is placed as a subclass of MSX1 subclass.
Knockout experiments with mice have shown a link to MSX 1 to failure to form teeth , and craniofacial abnormalities including absence alveolar bone in the jaws and disturbances in the formation of the parietal, nasal, frontal, cleft palate and malleus of middle ear.


To test the null hypothesis

MSX 1 gene mutation causes orofacial clefting.


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

The Inclusion criteria for the study was

Direct association of MSX 1 gene mutation to orofacial clefting

Human subjects with Cleft


Pub med showed 5, Science direct 79 and Cochrane 1 articles.

Further using the inclusion criteria, 5 articles were selected


The Role of MSX 1 gene  in Human orofacial clefting has always been debated , this systematic review was designed to find if there were any human studies that implicated orofacial clefting to the MSX 1 gene . In all 4 studies have implicated a direct relation to orofacial clefting. These studies have covered most of the populations around the world. AC Lidral and BC Reising2  found  a Met61Lys substitution  in two siblings in a big  family with autosomal-dominant tooth agenesis. Venkatesh S Prasad and Venkatesh Shivani3 found a novel  mutation (414G to T) in a south Indian population . Seishi Yamaguchi et al 5 found two  MSX1 variants with an amino acid substitution ; Thr174Ile (T174I) of a  hypodontia case and Leu205Arg of a   familial oligodontia case in a Japanese Population. Derya Ceyhan , Zuhal Kirzioglu and Nilufer Sahin Calapoglu6 reported mutations in the MSX 1 gene from a predominant Turkish population.


MSX1 gene which is a homeobox gene has been implicated in the formation of orofacial clefting. Several human studies have shown mutations in different populations.


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

Conflict of Interest

There is no conflict of Interest.


  1. Carter,C.O; Genetics of Common Disorders;Br.Med.Bul.,25,52,1969
  2. A.C . Lidral and B.C. Reising , The Role of MSX1 in Human tooth agenesis ,J Dent Res.2002;81(4):274-278.
  3. Venkanna S Prasad ,Venkatesh Shivani , Genetic significance of muscle segment homeo box1 gene in South Indian population for cleft lip and palate, Indian Journal of Human genetics.2012 sept –Dec;18(3):332-339.
  4. Ankola AV, Nagesh L, Hedge P, Karibasappa GN , Primary dentition status and treatment needs of children with cleft lip and/or palate. J Indian Soc Pedod Prev Dent. 2005; 23:80–82
  5. Yamaguchi S, Machida J, Kamamoto M, Kimura M, Shibata A, Tatematsu T, et al. Characterization of Novel MSX1 Mutations Identified in Japanese Patients with Nonsyndromic Tooth Agenesis.2014  PLoS ONE 9(8): e102944.
  6. Derya Ceyhan , Zuhal Kirzioglu and Nilufer Salin Calapoglu , Mutations in the Msx1 gene in Turkish Children with non –syndromic tooth agenesis and other dental anomalies.Indian J Dental. 2014 Oct –Dec ;5 (4): 172-182
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