Albright hereditary osteodystrophy (AHO) is a rare genetic disorder caused by heterozygous inactivating mutations in GNAS, the gene encoding the ? chain of Gs (G?s), and is associated with short stature, brachydactyly, subcutaneous ossifications, and cognitive deficits. AHO patients with GNAS mutations on maternally inherited alleles manifest resistance to multiple hormones (e.g. PTH, TSH, LH, FSH, GHRH) as well as obesity, a variant termed pseudohypoparathyroidism type 1a (PHP1a), due to paternal imprinting of G?s transcripts in specific tissues. AHO patients with GNAS mutations on paternally inherited alleles have the same phenotype but without hormonal resistance and marked obesity, a variant termed pseudopseudo- hypoparathyroidism (PPHP). Although both PHP1a and PPHP have been described as displaying cognitive deficits, we have found that patients with PHP1a lead compromised lives academically and socially, whereas those with PPHP do not. Based on preliminary data in a large cohort of patients with AHO as well as a mouse model, we hypothesize that the neurocognitive and psychosocial impairments observed in AHO are specific to PHP1a and may be secondary to imprinting in the brain.
The aims of this study are four-fold and will be examined by forming a new collaboration between Dr. Germain-Lee, who has expertise in AHO (and established the Albright Clinic at Kennedy Krieger Institute), and Drs. Mahone and Ramos (married name, Scarborough), who have expertise in neurocognitive and psychosocial assessments. First, we plan to examine children and adults with PHP1a systematically for neurocognitive and psychosocial dysfunction. Second, we will compare PHP1a patients with PPHP patients in order to define the differences in these populations which have previously been assumed as similar in terms of these parameters. Third, because the patients being examined in this study have had or will have DNA and transformed lymphocytes banked and mutation analyses performed, we can begin to correlate the neurocognitive and psychosocial phenotypes with genotypes as well as with levels of G?s protein/message levels and G?s activity. Finally, we will correlate these phenotypes/genotypes with hormonal and metabolic parameters, providing a unique opportunity to link cognition and behavior to endocrine function as well as examine potential sexual dimorphisms. The overall goals of this study are to define the neurocognitive and psychosocial phenotypes in PHP1a versus PPHP and to establish the role of imprinting and G protein-coupled signaling, as well as genotype, sex, and endocrine function, in the etiology of the differences that are found. This study may reveal disorders unique to PHP1a and therefore target management more specifically, leading to improvements in the treatment and quality of life of these patients. In addition, the specific cognitive and behavioral phenotypes found in PHP1a are likely to be significant problems in the general population, and their mechanisms may be further elucidated through investigations of the role of imprinting of GNAS and G protein-coupled signaling.

Public Health Relevance

Secondary to tissue-specific paternal imprinting of the gene encoding the alpha chain of Gs, patients with Albright hereditary osteodystrophy who inherit mutations from their maternal allele have pseudohypoparathyroidism type 1a (PHP1a) and are resistant to multiple G protein-coupled hormones, whereas patients who inherit mutations from their paternal allele have pseudopseudohypoparathyroidism and lack hormonal resistances. Based on our data we hypothesize that neurocognitive and behavioral dysfunctions are more prevalent in PHP1a, most likely secondary to imprinting in the brain, and that G protein- coupled signaling may play a role in neurocognitive and psychosocial functioning.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Developmental Brain Disorders Study Section (DBD)
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Kau, Alice S
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University of Connecticut
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Salemi, Parissa; Skalamera Olson, Julie M; Dickson, Lauren E et al. (2018) Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype, Inheritance, Sex, Age, Hormonal Status, and BMI. J Clin Endocrinol Metab 103:158-168
Mahone, E Mark; Crocetti, Deana; Tochen, Laura et al. (2016) Anomalous Putamen Volume in Children With Complex Motor Stereotypies. Pediatr Neurol 65:59-63