RESUMO
BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).
Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação , Obesidade Infantil/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Adolescente , Estatura , Criança , Cromograninas/genética , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/deficiência , Humanos , Masculino , Mutação de Sentido Incorreto , Receptores da Tireotropina/metabolismo , Transdução de Sinais , Sequenciamento do ExomaRESUMO
Focal entrapment of the ulnar nerve occurs most frequently in the region of the elbow, at the ulnar groove or beneath the humeroulnar aponeurosis. Surgical treatment commonly involves transposition of the nerve anterior to the medial epicondyle, in the antecubital fossa. Symptoms may recur after surgery, and, to assess their etiology, we studied 10 patients with recurrent ulnar symptoms after transposition. Conventional motor and sensory conduction studies were performed, as was mapping of nerve position using submaximal stimuli. In 9 of 10 patients, the ulnar nerve at the elbow was located adjacent to the medial epicondyle, rather than in the antecubital fossa. Focal slowing in the region of the elbow was noted in 8 patients, and an additional site of focal slowing was found in the forearm in 3 patients. We conclude that in patients with recurrent symptoms after ulnar nerve transposition postoperative position of the ulnar nerve may be medial, often near the medial epicondyle. This location may predispose the nerve to recurrent trauma or cause traction on the nerve at more distal locations within the forearm. The prevalence of this medial location of the ulnar nerve in asymptomatic postsurgical patients is unknown.