Growth Hormone Receptor Sequence Changes Do Not Play a Role in Determining Height in Children with Idiopathic Short Stature

Abstract

Background/Aims: In children with short stature, in whom growth hormone deficiency has been excluded, the presence of a normal or elevated growth hormone concentration concomitant with low insulin-like growth factor I suggests growth hormone insensitivity (GHI). Previous reports suggest that heterozygous mutations in the growth hormone receptor gene (GHR) may account for about 5% of children with idiopathic short stature (ISS). In the present study we have attempted to determine whether mutations in the GHR explain the short stature and growth retardation in a cohort of children with ISS and characteristics suggesting GHI. Methods: For the present study 33 children with clinical and biochemical characteristics of GHI were selected from a cohort of 150 children of short stature. Molecular analysis of the GHR was performed using a single-strand conformation polymorphism technique and sequencing. Ten different sequence changes in 19 (58%) out of 33 children were identified, 9 of them novel and 1 that had been described previously. Results: Two changes were found in exons 2 and 6. The known polymorphism of exon 6 (G168) was significantly more common in the control subjects than in our study group (63.5 vs. 30%; p < 0.0001). In the intronic sequences 8 previously undescribed DNA changes were found. The screening of the affected children’s family members revealed that both normal and short stature members carried the same variants. The study group did not significantly differ from the controls in retention (GHRfl) or exclusion (GHRd3) of exon 3. Conclusion: Our study suggests that sequence changes of the GHR are common in children with ISS. The presence of these sequence changes in the control subjects as well as in normal stature family members indicates that these changes represent a simple polymorphism of the GHR. Such DNA changes are more prevalent than previously recognized, and they do not seem to play a contributory role in the etiology of short stature.

GHR exon 3 polymorphism: Association with type 2 diabetes mellitus and metabolic disorder

“…It is of interest that these studies mainly present minor allele frequencies (MAF) less than our NGT samples, which may be explained by the metabolic aberrations that coincide with linear growth defects. The increased MAF observed in the controls of the study from Israel [23] may suggest population differences.…”

Heterozygous GHR gene mutation in a child with idiopathic short stature

“…However, it is uncertain whether heterozygous mutations in GHR play a major role in determining growth (18,19).…”

Idiopathic short stature: Clinical-diagnostic criteria

“…Ìóòàö³¿ ó ä³ëÿíö³ ãåíà ÃÐ-ðåöåïòîðà, ÿêèé êîäóº ïîçàêë³òèííèé äîìåí ðåöåïòîðà, áóëî âèÿâëåíî ó 4 ³ç 14 ä³òåé ³ç íèçüêîðîñë³ñòþ, àëå â aeîäíî¿ ç 24 çäîðîâèõ îñ³á. Òîae áóëî çðîáëåíî âèñíîâîê, ùî ó äåÿêèõ ä³òåé, õâîðèõ íà ²Í, º ìîaeëèâîþ ÷àñòêîâà íå-÷óòëèâ³ñòü äî ÃÐ âíàñë³äîê ìóòàö³é ó ãåí³ ÃÐ-ðåöåïòîðà [7,8]. Ó õâîðèõ íà ²Í ³ç íèçüêèì âì³ñòîì ÃÐ-çâ'ÿçóþ÷îãî á³ëêà âèçíà÷àâñÿ òàêîae íèae÷èé ð³âåíü ²×Ð-1 ó êðîâ³ ïîð³âíÿíî ç òàêèìè ae õâîðèìè, àëå ç íîðìàëüíèì âì³ñòîì ÃÐ-çâ'ÿçó-þ÷îãî á³ëêà [9].…”