Early-Onset Obesity: Unrecognized First Evidence for GNAS Mutations and Methylation Changes

Grüters-Kieslich, Annette; Reyes, Monica; Sharma, Amita; Demirci, Cem; DeClue, Terry; Lankes, Erwin; Tiosano, Dov; Schnabel, Dirk; Jüppner, Harald

doi:10.1210/jc.2017-00395

Cited by 26 publications

(24 citation statements)

References 45 publications

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“…Obesity is well known to be associated with PHP1A as exemplified by the largest study to date conducted in adults affected by this disorder, showing an average body mass index (BMI) Z ‐score of 1.7 ± 0.2 with two‐thirds of the patients meeting the criteria for obesity . In addition, early‐onset obesity has been observed in case reports and small series of patients with PHP1B …”

Section: Introductionmentioning

confidence: 98%

“…It has been frequently reported that patients affected by PHP1A and PPHP have adult heights that are approximately –2.5 and –2.3 SD, respectively, below average; growth delay is already present at birth in both diseases, particularly in PPHP patients . By contrast, final adult heights of AD‐PHP1B and spor‐PHP1B patients are described as “normal” in most reports despite recent descriptions of enhanced fetal growth and case reports of postnatal overgrowth (a summary of the evidence available in the literature for pre‐ and postnatal growth in PHP1A, PPHP, and PHP1B is provided in Supplemental Table S1). Obesity is well known to be associated with PHP1A as exemplified by the largest study to date conducted in adults affected by this disorder, showing an average body mass index (BMI) Z ‐score of 1.7 ± 0.2 with two‐thirds of the patients meeting the criteria for obesity .…”

Section: Introductionmentioning

confidence: 99%

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Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity

Hanna

Grybek

Nanclares

et al. 2018

Journal of Bone and Mineral Research

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Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations, and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to PTH resistance, PHP1A and PHP1B patients may display early-onset obesity. As early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length z-score PHP1A: −1.1±1.8; PPHP: −3.0±1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early post-natal overgrowth (height z-score at 1 year: 2.2±1.3 and 1.3±1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (z-score for both: −0.4±1.1). Early-onset obesity characterizes GNAS alterations and is associated to significant overweight and obesity in adults (BMI z-score: 1.4±2.6, 2.1±2.0, and 1.4±1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsα expression is a contributing factor.. The growth impairment in PHP1A/PPHP may be due to Gsα haploinsufficiency in the growth plates; the paternal XLαs transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity

Hanna

Grybek

Nanclares

et al. 2018

Journal of Bone and Mineral Research

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“…Pseudohypoparathyroidism (PHP) and related disorders have been associated with early-onset obesity (1,2). These diseases, which can present with highly variable clinical findings (3), are caused by a defect in the stimulatory G protein-cAMPsignaling pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Early-onset obesity can be the first and only evidence for pseudohypoparathyroidism (2,5). Several mechanisms can be responsible for the excessive weight gain.…”

Section: Introductionmentioning

confidence: 99%

“…In patients with PHP1A, reduced energy expenditure caused by the decreased Gsα-mediated signaling in brown or beige fat cells, as well as impaired signaling at the melanocortin 4 receptor leading to hyperphagia and thus increased caloric intake have been proposed as important mechanisms leading to obesity (6)(7)(8). Furthermore, the resistance to TSH and growth hormonereleasing-hormone may play a role in the development of obesity (2). Early-onset and childhood obesity has also been observed in PHP1B (1,9).…”

Section: Introductionmentioning

confidence: 99%

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GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children

et al. 2020

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Context: Pseudohypoparathyroidism type Ia (PHP1A) is caused by inactivating mutations involving GNAS exons 1-13, encoding the alpha-subunit of the stimulatory G protein (Gsα). Particularly PHP1A, but also other disorders involving the Gsα-cAMPsignaling pathway, have been associated with early-onset obesity. Thus, patients with mutations in the genes encoding PDE4D and PRKAR1A can also be obese. Furthermore, epigenetic GNAS changes, as in pseudohypoparathyroidism type Ib (PHP1B), can lead to excessive weight. Objective: Search for genetic variants in GNAS, PDE4D, and PRKAR1A and for methylation alterations at the GNAS locus in Finnish subjects with isolated severe obesity before age 10 years. Methods: Next generation sequencing to identify pathogenic variants in the coding exons of GNAS, PDE4D, and PRKAR1A; Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-sensitive MLPA (MS-MLPA) to search for deletions in GNAS and STX16, and for epigenetic changes at the four differentially methylated regions (DMR) within GNAS. Results: Among the 88 subjects (median age 13.8 years, median body mass index Z-score +3.9), we identified one rare heterozygous missense variant of uncertain significance in the XL exon of GNAS in a single patient. We did not identify clearly pathogenic variants in PDE4D and PRKAR1A, and no GNAS methylation changes were detected by MS-MLPA. Conclusions: Our results suggest that coding GNAS mutations or methylation changes at the GNAS DMRs, or coding mutations in PDE4D and PRKAR1A are not common causes of isolated childhood obesity in Finland.

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Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion

Kiuchi

Reyes

Jüppner

2020

Journal of Bone and Mineral Research

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Preferential transmission of a genetic mutation to the next generation, referred to as transmission ratio distortion (TRD), is well established for several dominant disorders, but underlying mechanisms remain undefined. Recently, TRD was reported for patients affected by pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism. To determine whether TRD is observed also for autosomal dominant pseudohypoparathyroidism type Ib (AD‐PHP1B), we analyzed kindreds with the frequent 3‐kb STX16 deletion or other STX16/GNAS mutations. If inherited from a female, these genetic defects lead to loss‐of‐methylation at exon A/B alone or at all three differentially methylated regions (DMR), resulting in parathyroid hormone (PTH)‐resistant hypocalcemia and hyperphosphatemia and possibly resistance to other hormones. In total, we investigated 212 children born to 80 females who are unaffected carriers of a STX16/GNAS mutation (n = 47) or affected by PHP1B (n = 33). Of these offspring, 134 (63.2%) had inherited the genetic defect (p = .00012). TRD was indistinguishable for mothers with a STX16/GNAS mutation on their paternal (unaffected carriers) or maternal allele (affected). The mechanisms favoring transmission of the mutant allele remain undefined but are likely to include abnormalities in oocyte maturation. Search for mutations in available descendants of males revealed marginally significant evidence for TRD (p = .038), but these analyses are less reliable because many more offspring of males than females with a STX16/GNAS mutation were lost to follow‐up (31 of 98 versus 6 of 218). This difference in follow‐up is probably related to the fact that inheritance of a mutation from a male does not have clinical implications, whereas inheritance from an affected or unaffected female results in PHP1B. Lastly, affected PHP1B females had fewer descendants than unaffected carriers, but it remains unclear whether abnormal oocyte development or impaired actions of reproductive hormones are responsible. Our findings highlight previously not recognized aspects of AD‐PHP1B that are likely to have implications for genetic testing and counseling. © 2020 American Society for Bone and Mineral Research (ASBMR).

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Early-Onset Obesity: Unrecognized First Evidence for GNAS Mutations and Methylation Changes

Cited by 26 publications

References 45 publications

Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity

Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity

GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children

Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion

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