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De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features.
Mullegama, Sureni V; Kiernan, Kaitlyn A; Torti, Erin; Pavlovsky, Ethan; Tilton, Nicholas; Sekula, Austin; Gao, Hua; Alaimo, Joseph T; Engleman, Kendra; Rush, Eric T; Blocker, Karli; Dipple, Katrina M; Fettig, Veronica M; Hare, Heather; Glass, Ian; Grange, Dorothy K; Griffin, Michael; Phornphutkul, Chanika; Massingham, Lauren; Mehta, Lakshmi; Miller, Danny E; Thies, Jenny; Merritt, J Lawrence; Muller, Eric; Osmond, Matthew; Sawyer, Sarah L; Slaugh, Rachel; Hickey, Rachel E; Wolf, Barry; Choudhary, Sanjeev; Simonovic, Miljan; Zhang, Yueqing; Palculict, Timothy Blake; Telegrafi, Aida; Carere, Deanna Alexis; Wentzensen, Ingrid M; Morrow, Michelle M; Monaghan, Kristin G; Yang, Jun; Juusola, Jane.
Afiliación
  • Mullegama SV; GeneDx, Gaithersburg, MD 20877, USA; Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA. Electronic address: smullegama@genedx.com.
  • Kiernan KA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • Torti E; GeneDx, Gaithersburg, MD 20877, USA.
  • Pavlovsky E; Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA.
  • Tilton N; Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA.
  • Sekula A; Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA.
  • Gao H; GeneDx, Gaithersburg, MD 20877, USA.
  • Alaimo JT; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, USA; Department of Pediatrics, University of Missouri Kansas City, School of Medicine, Kansas City, MO, USA; Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO, USA.
  • Engleman K; Department of Pediatrics, University of Missouri Kansas City, School of Medicine, Kansas City, MO, USA; Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO, USA.
  • Rush ET; Department of Pediatrics, University of Missouri Kansas City, School of Medicine, Kansas City, MO, USA; Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO, USA; Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, KS, USA.
  • Blocker K; Division of Clinical Genetics, Stanford Children's Health, San Francisco, CA, USA.
  • Dipple KM; Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
  • Fettig VM; Center for Inherited Cardiovascular Disease, Cardiovascular Genetics Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Hare H; Northeastern Ontario Medical Genetics Program, Health Sciences, North Sudbury, ON, Canada.
  • Glass I; Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
  • Grange DK; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
  • Griffin M; Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA.
  • Phornphutkul C; Division of Genetics, Department of Pediatrics, Alpert School of Medicine at Brown University, Providence, RI, USA.
  • Massingham L; Division of Genetics, Department of Pediatrics, Alpert School of Medicine at Brown University, Providence, RI, USA.
  • Mehta L; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Miller DE; Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
  • Thies J; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
  • Merritt JL; Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.
  • Muller E; Division of Clinical Genetics, Stanford Children's Health, San Francisco, CA, USA.
  • Osmond M; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
  • Sawyer SL; Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
  • Slaugh R; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
  • Hickey RE; Department of Pediatrics, Division of Genetics, Birth Defects and Metabolism, Anne & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
  • Wolf B; Department of Pediatrics, Division of Genetics, Birth Defects and Metabolism, Anne & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
  • Choudhary S; Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA.
  • Simonovic M; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • Zhang Y; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Palculict TB; GeneDx, Gaithersburg, MD 20877, USA.
  • Telegrafi A; GeneDx, Gaithersburg, MD 20877, USA.
  • Carere DA; GeneDx, Gaithersburg, MD 20877, USA.
  • Wentzensen IM; GeneDx, Gaithersburg, MD 20877, USA.
  • Morrow MM; GeneDx, Gaithersburg, MD 20877, USA.
  • Monaghan KG; GeneDx, Gaithersburg, MD 20877, USA.
  • Yang J; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: junyang@utmb.edu.
  • Juusola J; GeneDx, Gaithersburg, MD 20877, USA.
Am J Hum Genet ; 111(4): 778-790, 2024 04 04.
Article en En | MEDLINE | ID: mdl-38531365
ABSTRACT
Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastornos del Neurodesarrollo / Discapacidad Intelectual / Anomalías Musculoesqueléticas Límite: Animals / Child / Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastornos del Neurodesarrollo / Discapacidad Intelectual / Anomalías Musculoesqueléticas Límite: Animals / Child / Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos