Clinical and functional studies of MTOR variants in Smith-Kingsmore syndrome reveal deficits of circadian rhythm and sleep-wake behavior.

Autor:	Liu AC; Department of Physiology and Aging, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: andrew.liu@ufl.edu., Shen Y; Department of Physiology and Aging, University of Florida College of Medicine, Gainesville, FL 32610, USA., Serbinski CR; Divisions of Human Genetics, Neurology, Immunobiology, Pediatric Otolaryngology, and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Genetics, Genomics & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA., He H; Department of Physiology and Aging, University of Florida College of Medicine, Gainesville, FL 32610, USA., Roman D; Department of Physiology and Aging, University of Florida College of Medicine, Gainesville, FL 32610, USA., Endale M; Department of Physiology and Aging, University of Florida College of Medicine, Gainesville, FL 32610, USA., Aschbacher-Smith L; Divisions of Human Genetics, Neurology, Immunobiology, Pediatric Otolaryngology, and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., King KA; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA., Granadillo JL; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA., López I; Pediatric Neurology Unit, Department of Neurology, Clínica Las Condes, Santiago, Chile., Krueger DA; Divisions of Human Genetics, Neurology, Immunobiology, Pediatric Otolaryngology, and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Dye TJ; Divisions of Human Genetics, Neurology, Immunobiology, Pediatric Otolaryngology, and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Smith DF; Divisions of Pediatric Otolaryngology and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Sleep Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Center for Circadian Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Otolaryngology Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA., Hogenesch JB; Divisions of Human Genetics, Neurology, Immunobiology, Pediatric Otolaryngology, and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Prada CE; Divisions of Human Genetics, Neurology, Immunobiology, Pediatric Otolaryngology, and Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Genetics, Genomics & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA; Department of Pediatrics, Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, USA. Electronic address: cprada@luriechildrens.org.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2024 Oct 10; Vol. 5 (4), pp. 100333. Date of Electronic Publication: 2024 Jul 17.
DOI:	10.1016/j.xhgg.2024.100333
Abstrakt:	Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent nine MTOR pathogenic variants. We conducted a detailed natural history study and found pathophysiological deficits among individuals with SKS in addition to the common neurodevelopmental symptoms. These symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, indicative of homeostatic imbalance. To characterize these variants, we developed cell models and characterized their functional consequences. We showed that these SKS variants display a range of mechanistic target of rapamycin (mTOR) activities and respond to the mTOR inhibitor, rapamycin, differently. For example, the R1480_C1483del variant we identified here and the previously known C1483F are more active than wild-type controls and less responsive to rapamycin. Further, we showed that SKS mutations dampened circadian rhythms and low-dose rapamycin improved the rhythm amplitude, suggesting that optimal mTOR activity is required for normal circadian function. As SKS is caused by gain-of-function mutations in MTOR, rapamycin was used to treat several patients. While higher doses of rapamycin caused delayed sleep-wake phase disorder in a subset of patients, optimized lower doses improved sleep. Our study expands the clinical and molecular spectrum of SKS and supports further studies for mechanism-guided treatment options to improve sleep-wake behavior and overall health. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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