Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity.
BACKGROUND
Obesity is a prominent feature of Albright hereditary osteodystrophy (AHO), a disorder caused by heterozygous GNAS mutations that disrupt the stimulatory G protein alpha-subunit Galpha(s). Because Galpha(s) is paternally imprinted in certain hormone target tissues, maternal inheritance of AHO leads to multihormone resistance [pseudohypoparathyroidism type 1a (PHP1a)], whereas paternal inheritance leads to AHO alone [pseudopseudohypoparathyroidism (pseudoPHP)]. Classically, the obesity in AHO is described as occurring similarly in both conditions.


METHODS
This observational study was conducted at the General Clinical Research Center, Johns Hopkins University School of Medicine; National Institutes of Health.


METHODS
Fifty-three patients with AHO (40 with PHP1a and 13 with pseudoPHP) and two with progressive osseous heteroplasia were studied.


METHODS
Main outcome measures were weight and height sd score (SDS), body mass index (BMI) percentiles, and BMI z-scores.


RESULTS
Patients with PHP1a had significantly greater mean weight SDS, BMI percentages, and BMI z-scores compared with patients with pseudoPHP. These differences in BMI were secondary to adipose content based on dual energy x-ray absorptiometry analysis. The mean BMI z-score +/- sem for PHP1a was 2.31 +/- 0.18 compared with 0.65 +/- 0.31 in pseudoPHP (P = 0.000032). Twenty-five of 40 (62.5%) patients with PHP1a had mean BMI z-scores greater than two SDS above the mean, whereas no patients with pseudoPHP had BMI z-scores in this range.


CONCLUSIONS
Although the AHO phenotype for PHP1a and pseudoPHP has been thought to be similar, we have found that obesity is a more prominent feature in PHP1a than in pseudoPHP and that severe obesity is characteristic of PHP1a specifically. These findings may implicate paternal imprinting of Galpha(s) in the development of human obesity.
Long
Dominique N
DN
Division of Pediatric Endocrinology, Department of Pediatrics, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
McGuire
Sarah
S
Levine
Michael A
MA
Weinstein
Lee S
LS
Germain-Lee
Emily L
EL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D005220:Fathers; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D018392:Genomic Imprinting; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009765:Obesity / Q000150:complications / Q000235:genetics*; D011547:Pseudohypoparathyroidism / Q000150:complications* / Q000235:genetics*
D002864:Chromogranins; D044385:GTP-Binding Protein alpha Subunits; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs