Ghrelin and Its Receptor Gene Mutations Do Not Explain Growth or Weight Problems in Israeli Children | Research

The takeaway

Screening 98 Israeli children with growth or weight disorders found no disease-causing mutations in ghrelin or its receptor GHSR, despite these genes' known roles in appetite and growth.

0 pathogenic mutations
Despite screening 98 children with growth or weight abnormalities, no functionally significant mutations were found in ghrelin or GHSR coding regions

What the researchers found

Among 98 children with growth or weight abnormalities, seven different sequence changes were identified in GHSR (two novel, five previously described), but none affected the protein-coding region. The ghrelin gene variant p.L72M was found in five patients but occurred at a higher rate in healthy controls, arguing against a pathogenic role.

Despite a high overall rate of sequence variations in both ghrelin and GHSR, none of the changes were functionally significant, indicating that mutations in these genes are not a common explanation for short stature, failure to thrive, growth hormone deficiency, or obesity in this population.

Why it matters

Understanding the genetic basis of growth and weight disorders in children is crucial for developing targeted treatments. While ghrelin is a major regulator of appetite and growth, this study demonstrates that simply looking for mutations in the ghrelin system is not a productive diagnostic strategy for most children with these conditions. This redirects attention toward other genetic and environmental factors and highlights the complexity of growth regulation beyond single-gene explanations.

How the study worked

Ninety-eight children (38 female, 60 male) from an Israeli population were enrolled across four diagnostic groups: failure to thrive (n=9), growth hormone deficiency (n=44), idiopathic short stature (n=22), and obesity (n=23). The coding exons of both the ghrelin and GHSR genes were screened for mutations by direct DNA sequencing. Identified variants were compared against previously reported mutations and control population frequencies.

What this study cannot tell us

The sample size of 98 is relatively small for a genetic screening study, limiting power to detect rare pathogenic variants. The study only sequenced coding exons, so regulatory mutations or deep intronic variants could have been missed. The population was from a single Israeli center, so results may not apply to other ethnic groups. Functional studies of the identified variants were not performed.

How to read the evidence

This is a clinical genetic screening study with a clear methodology (direct sequencing) in a well-defined patient population. The negative result is informative but limited by the small sample size and coding-region-only approach.

When this study was published

Published in 2012, this study predates modern whole-exome and whole-genome sequencing approaches. Newer technologies could potentially identify variants missed by the targeted exon sequencing used here.

The bigger picture

This study adds to the growing body of evidence that common pediatric growth and weight disorders are not typically caused by single-gene mutations in the ghrelin signaling pathway. While rare GHSR mutations have been reported in individual cases of short stature and obesity, this population-based screening suggests they are not a major contributor. This informs the broader debate about monogenic versus polygenic contributions to growth regulation.

Questions still open

Could non-coding regulatory variants in ghrelin or GHSR contribute to growth and weight disorders in ways not detected by exon sequencing?
Are there other peptide hormone receptor genes that play a larger role in pediatric growth disorders?
Would larger-scale whole-exome or whole-genome studies in diverse populations reveal rare pathogenic ghrelin/GHSR variants?

Common questions

Why did researchers think ghrelin mutations might cause growth problems in children?

Ghrelin is sometimes called the 'hunger hormone' — it stimulates appetite and triggers growth hormone release. Since it plays such a central role in growth and weight regulation, scientists logically hypothesized that mutations disrupting ghrelin or its receptor could cause growth failure, short stature, or obesity in children. This study tested that hypothesis and found it doesn't hold for most cases.

Does this mean ghrelin isn't important for growth?

No — ghrelin is still critically important for appetite and growth regulation. What this study shows is that mutations in the ghrelin gene are rarely the cause when children have growth or weight problems. The conditions are likely driven by more complex interactions among many genes and environmental factors, rather than single mutations in the ghrelin system.

Read the original research

Ghrelin and growth hormone secretagogue receptor (GHSR) genes are not commonly involved in growth or weight abnormalities in an Israeli pediatric population.

Journal of pediatric endocrinology & metabolism : JPEM, 25(5-6), 537-40

View on PubMed ↗

Citation

Hess, Ora; Admoni, Osnat; Khayat, Morad; Elias, Gadir; Almagor, Tal; Shalev, Stavit-Allon; Tenenbaum-Rakover, Yardena. (2012). Ghrelin and growth hormone secretagogue receptor (GHSR) genes are not commonly involved in growth or weight abnormalities in an Israeli pediatric population.. Journal of pediatric endocrinology & metabolism : JPEM, 25(5-6), 537-40.