Mutation analysis of the muscarinic cholinergic receptor genes in isolated growth hormone deficiency type IB
| Autor: | Roberto Salvatori, Marco Martari, John A. Phillips, Cindy D. Holladay, Ali Mohamadi, Primus E. Mullis |
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| Rok vydání: | 2009 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism Clinical Biochemistry DNA Mutational Analysis Hypothalamus CHO Cells Biology medicine.disease_cause Transfection Biochemistry Endocrinology Cricetulus Gene Frequency Internal medicine Cricetinae Muscarinic acetylcholine receptor medicine Leukocytes Animals Humans Family Receptor Dwarfism Pituitary Gene Acetylcholine receptor Mutation Biochemistry (medical) Muscarinic acetylcholine receptor M3 Receptors Muscarinic Growth hormone secretion Pedigree IGHD Original Article |
| Zdroj: | The Journal of clinical endocrinology and metabolism. 94(7) |
| ISSN: | 1945-7197 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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