Mutation analysis of the muscarinic cholinergic receptor genes in isolated growth hormone deficiency type IB

Ali Mohamadi, Marco Martari, Cindy D. Holladay, John A. Phillips, Primus E. Mullis, Roberto Salvatori

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Background: Isolated GH deficiency (IGHD) is familial in 5-30% of patients. The most frequent form (IGHD-IB) has autosomal recessive inheritance, and it is known that it can be caused by mutations in the GHRH receptor (GHRHR) gene or in the GH gene. However, most forms of IGHD-IB have an unknown genetic cause. In normal subjects, muscarinic cholinergic stimulation causes an increase in pituitary GH release, whereas its blockade has the opposite effect, suggesting that a muscarinic acetylcholine receptor (mAchR) is involved in stimulating GH secretion. Five types of mAchR (M1-M5) exist. A transgenic mouse in which the function of the M3 receptor was selectively ablated in the central nervous system has isolated GH deficiency similar to animals with defective GHRH or GHRHR gene. Objective: We hypothesized that mAchR mutations may cause a subset of familial IGHD. Patients/Methods: After confirming the expression of M1-M5 receptor mRNA in human hypothalamus, we analyzed the index cases of 39 families with IGHD-IB for mutations in the genes encoding for the five receptors. Coding sequences for each of the five mAchRs were subjected to direct sequencing. Results: In one family, an affected member was homozygous for a M3 change in codon 65 that replaces valine with isoleucine (V65I). The V65I receptor was expressed in CHO cells where it had normal ability to transmit methacholine signaling. Conclusion: mAchR mutations are absent or rare (less than 2.6%) in familial IGHD type IB.

Original languageEnglish (US)
Pages (from-to)2565-2570
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Issue number7
StatePublished - Jul 2009

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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