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Mutation Analysis of the Muscarinic Cholinergic Receptor Genes in Isolated Growth Hormone Deficiency Type IB

Division of Endocrinology, Departments of Pediatrics (A.M.) and Medicine (M.M., R.S.), Johns Hopkins School of Medicine, Baltimore, Maryland 21287; Department of Pediatrics (C.D.H., J.A.P.), Vanderbilt University, Nashville, Tennessee 37240; and Department of Pediatrics (P.E.M.), University of Bern, CH-3010 Bern, Switzerland

Address all correspondence and requests for reprints to: Roberto Salvatori, M.D., Division of Endocrinology and Metabolism, Johns Hopkins School of Medicine, 1830 East Monument Street, Room 333, Baltimore, Maryland 21287. E-mail: salvator{at}jhmi.edu.

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.