Shortened Fingers and Toes: GNAS Abnormalities are Not the
                    Only Cause

Monica Reyes; Caroline Silve; Harald Jüppner

doi:10.1055/a-1047-0334

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2020; 128(10): 681-686
DOI: 10.1055/a-1047-0334

Review

Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause

Authors

Monica Reyes

¹Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Caroline Silve

²INSERM équipe “Génomiques et épigénétique des tumeurs rares”, Institut Cochin, Paris, France

³Centre de Référence des Maladies rares du Calcium et du Phosphore and Filière de Santé Maladies Rares OSCAR, AP-HP, Paris, France

⁴Service de Biochimie et Génétique Moléculaires, Hôpital Cochin, AP- HP, Paris, France
Harald Jüppner

¹Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

⁵Pediatric Nephrology Unit, MassGeneral Hospital for Children Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Abstract

The PTH/PTHrP receptor (PTHR1) mediates the actions of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) by coupling this G protein-coupled receptor (GPCR) to the alpha-subunit of the heterotrimeric stimulatory G protein (Gsα) and thereby to the formation of cAMP. In growth plates, PTHrP-dependent activation of the cAMP/PKA second messenger pathway prevents the premature differentiation of chondrocytes into hypertrophic cells resulting in delayed growth plate closure. Heterozygous mutations in GNAS, the gene encoding Gsα, lead to a reduction in cAMP levels in growth plate chondrocytes that is sufficient to cause shortening of metacarpals and/or -tarsals, i. e. typical skeletal aspects of Albright’s Hereditary Osteodystrophy (AHO). However, heterozygous mutations in other genes, including those encoding PTHrP, PRKAR1A, PDE4D, and PDE3A, can lead to similar or even more pronounced acceleration of skeletal maturation that is particularly obvious in hands and feet, and reduces final adult height. Genetic mutations other than those resulting in Gsα haploinsufficiency thus reduce intracellular cAMP levels in growth plate chondrocytes to a similar extent and thereby accelerate skeletal maturation.

Key words

PTH - PTHrP - PTH/PTHrP receptor - GNAS - alpha-subunit of the stimulatory G protein - genetic disease - acrodysostosis - cAMP signaling pathway - PRKAR1A - PDE4D - PDE3A - HDAC4

Full Text

References

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