Guanine nucleotide-binding protein α subunit hypofunction in children with short stature and disproportionate shortening of the 4th and 5th metacarpals.
BACKGROUND
GNAS encodes the α subunit of the stimulatory G protein (Gsα). Maternal inherited Gsα mutations cause pseudohypoparathyroidism type Ia (PHP-Ia), associated with shortening of the 4th and 5th metacarpals.


OBJECTIVE
Here we investigated the Gsα pathway in short patients with distinct shortening of the 4th and 5th metacarpals.


METHODS
In 571 children with short stature and 4 patients with PHP-Ia metacarpal bone lengths were measured. In identified patients we analysed the Gsα protein function in platelets, performed GNAS sequencing, and epigenetic analysis of four significant differentially methylated regions.


RESULTS
In 51 patients (8.9%) shortening of the 4th and 5th metacarpals was more pronounced than their height deficit. No GNAS coding mutations were identified in 20 analysed patients, except in 2 PHP-Ia patients. Gsα activity was reduced in all PHP-Ia patients and in 25% of the analysed patients. No significant methylation changes were identified.


CONCLUSIONS
Our findings suggest that patients with short stature and distinct metacarpal bone shortening could be part of the wide variety of PHP/PPHP, therefore it was worthwhile analysing the Gsα protein function and GNAS gene in these patients in order to further elucidate the phenotype and genotype of Gsα dysfunction.
Division of Paediatric Endocrinology, University Children's Hospital Heidelberg, Heidelberg, Germany.
Ioana Monica
IM
Inta
Daniela
D
Choukair
Sebastian
S
Bender
Carolin
C
Kneppo
Sabine
S
Knauer-Fischer
Kahina
K
Meyenburg
Boris
B
Ivandic
Stefan M
SM
Pfister
Markus
M
Bettendorf
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D056426:Genetic Loci; D006130:Growth Disorders / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D050279:Metacarpal Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D009929:Organ Size / Q000235:genetics; D011547:Pseudohypoparathyroidism / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D011859:Radiography