NEW YORK (GenomeWeb) – While characterizing a small X chromosome duplication implicated in gigantism, a National Institutes of Health-led team identified a recurrent gene mutation that appears to cause acromegaly — a related, rare condition in adults that involves excess growth hormone release by the pituitary gland.
As they reported in the New England Journal of Medicine last night, the researchers used a combination of array comparative genomic hybridization and targeted gene sequencing to assess samples from 43 individuals with gigantism.
In more than a dozen of the affected individuals, the team detected a previously described microduplication called Xq26.3 that seems to stem from chromosome replication hiccups. The microduplication turned up in individuals who developed gigantism symptoms at a young age, prompting the group to dub the associated pediatric condition as "X-linked acrogigantism," or X-LAG.
One of four genes in the region — the G-protein-coupled receptor coding gene GPR101 — was found at higher-than-usual levels in patient pituitary lesions. Further scrutiny of that gene in almost 250 more individuals with acromegaly uncovered a recurrent point mutation in GPR101 in more than 4 percent of those tested, bolstering the notion that the gene has a key role in regulating growth.
"Understanding how children grow is extraordinarily important, as an indicator of their general health and their future well-being," co-senior author Constantine Stratakis, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development's intramural research division, said in a statement.
From their findings so far, Stratakis added, the researchers are convinced that GPR101 is a "major" growth regulator.
Past studies have described syndromic forms of gigantism that do not involve pituitary gland glitches, Stratakis and colleagues explained, while non-syndromic forms of the disease often involve tumor growth and/or pituitary problems.
For instance, gigantism-causing pituitary growths known as adenomas have been linked to mutations in a gene called AIP, which codes for a protein that interacts with the aryl hydrocarbon receptor.
For their current study, the researchers focused on individuals who had gigantism, growth hormone hypersecretion, and pituitary lesions, but lacked obvious defects in the AIP gene.
The team started by testing five familial cases and 38 sporadic cases. Those sporadic cases included nine individuals with the Xq26.3 microduplication and 29 without, while four familial cases involved the microduplication.
The microduplication was exclusively identified amongst those who'd experienced disease onset early on in their childhood, the researchers explained. In contrast, individuals without the microduplication did not show signs of gigantism until after their fifth birthdays.
With the help of genome-wide aCGH on four familial and eight sporadic gigantism cases, the investigators determined that the chromosome X microduplication comes in a variety of slightly different sizes that consistently span three to four genes.
From breakpoint patterns present in the duplicated region, the team argued that the alteration may be introduced at some point during chromosome replication. Meanwhile its analysis of genes in the region hinted that the growth-related consequences of the microduplication are due to changes in expression of the GPR101 gene.
Through targeted sequencing tests on another 248 individuals with acromegaly, the researchers identified a recurrent mutation in the same gene in 11 cases — a substitution that was frequently found in tumor tissue from affected individuals.
Given the similarities between the symptoms seen in this validation group, the team speculated that the mutation likely boosts the activity of GPR101.
Indeed, rat pituitary cells transfected with a form of the gene carrying the mutation showed enhanced growth hormone secretion and proliferation, though more research is needed to understand how this genetic glitch shifts pituitary function.
"[O]ur results suggest that Xq26.3 microduplication is associated with a clinical syndrome of early-onset gigantism, which we have termed X-LAG," the study's authors concluded.
"An increased dose of GPR101 on chromosome Xq26.3 probably causes the disease," they explained, "and its activation by mutation occurs in patients with sporadic acromegaly."