GHR Gene Variant Influence on Craniofacial Morphology

“I526L” – Growth hormone receptor gene variant and its effect on craniofacial morphology.


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OBJECTIVES: To investigate the influence of GHR (Growth Hormone Receptor) gene variant (I526L) on craniofacial morphology.


The department of orthodontics, D.A.P.M.R.V.Dental College and Hospital, Bangalore, India. 30 randomly selected subjects, aged 20-30 years who were patients at D.A.P.M.R.V.Dental College & Hospital, Bangalore.


DNA was extracted from venous blood samples of all the subjects. The extracted DNA samples were subjected to polymerase chain reaction, where amplification of the selected gene segments was done and later these amplified products were subjected to restriction fragment length polymorphism using HpyCH4V restriction enzyme. Results were documented in specific bands with gel documentation centre. The effects of the gene variant on the 4 craniofacial morphologic parameters of anterior cranial base length, maxillary length, mandibular ramus length/height and mandibular length were obtained from lateral cephalograms and tabulated. Appropriate statistical analysis was carried out.


The results indicated that the subjects with I526L variant of GHR gene had a significantly greater mandibular ramus height. GHR gene variant I526L could be a genetic marker for mandibular ramus height.


Craniofacial morphologic parameters, Growth hormone receptor, Polymerase chain reaction, Restriction fragment length polymorphism.


The key to the determination of the etiology of malocclusion, and its treatability lies in the ability to differentiate the effect of genes and environment on the craniofacial skeleton in a particular individual. There are numerous ways in which the variant I526L could affect GHR activity. In addition to potentially causing direct changes in protein function, the variants could affect regulation of GHR, and in either case the variant could act singly or in combination with other single nucleotide polymorphisms (SNPs). The effect of these SNPs on GHR function and downstream gene expression should be clarified by further study. A study of gene polymorphisms in GHR would be useful in understanding genetic influences on craniofacial morphological determinants and helps in diagnosis and treatment in orthodontics to be delivered at a molecular level.


Growth hormone (GH) is a craniofacial morphologic determinant. Genetic influences are important in the determination of mandibular morphology, and growth hormone receptor (GHR) is believed to have an important influence on the growth of craniofacial bones. Responses to systemic GH therapy are time and site dependent in the craniofacial region, increasing growth, particularly in mandibular ramus. The growth hormone receptor gene is located on chromosome 5p13.1-p12 and is 87 Kb long, with 10 exons encoding 620 amino acids .1

Cartilage-mediated growth in the mandibular condyle is known to play an important role in the determination of growth and morphology of the mandible. GH treatment accelerates craniofacial growth, especially in the mandibular condyle where cartilage-mediated growth occurs. GH receptors have been shown to be present in the mandibular condyle.2

A single-nucleotide polymorphism (SNP) or a gene variant or a missense mutation is a DNA sequence variation occurring when a single nucleotide A, T, C, or G in the genome differs between members of a species or between paired chromosomes in an individual.Sequence analysis showed that 6 SNPs/gene variants were identifiable in the GHR gene in Chinese population, out of which C422F, P477T, I526L, and P561T are SNPs with significant effects.1

The purpose of this study was to investigate the single nucleotide polymorphisms (SNPs) (I526L) in GHR gene and examine the relationship between GHR gene variant I526L and craniofacial morphology.


The sample consisted of 30 randomly selected subjects, aged 20-30 years who were patients at D.A.P.M.R.V.Dental College & Hospital, Bangalore.

After clearance from ethical committee, venous Blood samples (2ml) were obtained from the subjects with informed consent.

Lateral cephalograms of these subjects obtained as a part of routine treatment protocol were used.

Method of Polymerase Chain Reaction and Restriction fragment length polymorphism was employed to deduce the genotypes.

After collection and storage of blood samples, genomic DNA was isolated and Polymerase Chain Reaction Test was performed using specific primers (rs6180).

This was followed by digestion with Restriction Enzymes HpyCH4V.Cephalometric measurements were carried out on standardized lateral cephalograms using Burstone analysis norms3 to measure the craniofacial parameters of anterior cranial base length, maxillary length, mandibular ramus length/height and mandibular length. The results were computed by correlating PCR results with the cephalometric craniofacial measurement values. Statistical analysis using Z test for proportions was carried out to test the level of significance. The Statistical software namely SPSS 11.0 and Systat 8.0 were used for the analysis of the data.


The initial PCR product of the GHR gene variant I526L was obtained for the thirty subjects. The size of this PCR product was 602bp.

Photograph 1: Initial PCR Product of GHR gene variant I526L (602bp).

This was then subjected to digestion with the specific restriction enzyme HpyCH4V for I526L. After digestion, the 602 bp products were completely digested in 16 subjects whereas 14 subjects showed incomplete/no digestion. So the presence of variant I526L was shown in 14 subjects and absence of variant I526L in 16 subjects.

Association of the presence or absence of variant I526L with increased, normal and decreased measurements (when compared with norms) of all four craniofacial parameters were tabulated.

Table 1: Table comparing the P-values of samples with presence of I526L variant with respect to normal v/s increased, normal v/s decreased and increased v/s decreased mandibular ramus length

Graph 1:Presence and absence of variant I526L in samples with normal,increased and decreased ramus height.

Out of the four craniofacial parameters investigated association of presence of variant with mandibular ramus height was found to be statistically significant(P=0.002,P<0.001).


In the Human Gene Mutation Database, 56 different GHR gene mutations, including 32 missense and nonsense mutations, have been registered.4 In a few reports concerning the effect of GHR gene mutations on craniofacial growth, Chinese Han individuals with a genomic polymorphism at codon 526 of the GHR gene had a greater mandibular ramus length. Presence of variant I526L was seen in 46.67% of the samples. This is in accordance with a study done in Chinese population which showed I526L to have the highest heterozygosity of all the variants i.e 47.6%.1

A significant association was seen with presence of I526L variant and increased ramus height. (P=0.002, <0.001).Presence of I526L was seen in 71% of the samples with increased ramus. Since mandibular ramus height is a parameter affected by growth at the condylar cartilage, and GHR has its effect on condyle, the presence of I526L can affect the same. This is in accordance with the study done by Kjellberg H,Wikland KA and Zhou et al .1,5

Evaluation of site specific relationship between various craniofacial morphological determinants and the variant I526L showed significant association of increased ramus height with presence of I526L and this is in accordance with the study done by Zhou et al in Chinese population.1,5 This is also in accordance with a study done on 39 cephalometric variables which are under strong genetic control which showed strong genetic correlation with the vertical parameters.6Since mandibular ramus is the only vertical parameter included in the study it is seen to have a significant correlation with the variants.

Further studies with all the four SNPs i.e. C422F, P477T, P561T and I526L can be carried out for a more detailed analysis of their influence on craniofacial morphology .


This study indicates that subjects with I526L variant of GHR gene had a significantly greater mandibular ramus height. Influence of I526L is site specific as presence of I526L has an influence on increasing ramus height out of the four craniofacial parameters.GHR gene variant I526L could be a genetic marker for mandibular ramus height.

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