2. Academic Validation
  3. Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities

Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities

  • Am J Hum Genet. 2020 Feb 6;106(2):246-255. doi: 10.1016/j.ajhg.2020.01.002.
Matias Wagner 1,  Yuliya Skorobogatko 2,  Ben Pode-Shakked 3,  Cynthia M Powell 4,  Bader Alhaddad 5,  Annette Seibt 6,  Ortal Barel 7,  Gali Heimer 8,  Chen Hoffmann 9,  Laurie A Demmer 10,  Yezmin Perilla-Young 4,  Marc Remke 11,  Dagmar Wieczorek 12,  Tharsini Navaratnarajah 6,  Peter Lichtner 13,  Dirk Klee 14,  Hanan E Shamseldin 15,  Fuad Al Mutairi 16,  Ertan Mayatepek 6,  Tim Strom 5,  Thomas Meitinger 17,  Fowzan S Alkuraya 15,  Yair Anikster 3,  Alan R Saltiel 2,  Felix Distelmaier 18
Affiliations

Affiliations

  • 1 Institute of Human Genetics, Technical University München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute for Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany. Electronic address: [email protected].
  • 2 Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
  • 3 Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel.
  • 4 Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27599, USA.
  • 5 Institute of Human Genetics, Technical University München, 81675 Munich, Germany.
  • 6 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
  • 7 Genomics Unit, Sheba Cancer Research Center, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 8 Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 9 Sackler Faculty of Medicine, Tel-Aviv University, 6997801 Tel-Aviv, Israel; Department of Radiology, Sheba Medical Center, 52621 Tel-Hashomer, Israel.
  • 10 Medical Genetics, Atrium Health Levine Children's Hospital, Charlotte, NC, 28203, USA.
  • 11 Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, 40225 Düsseldorf, Germany.
  • 12 Institute of Human Genetics, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
  • 13 Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 14 Department of Diagnostic and Interventional Radiology, Heinrich-Heine University, 40225 Düsseldorf, Germany.
  • 15 Department of Genetics, King Faisal Specialist Hospital and Research Center, 12713 Riyadh, Saudi Arabia.
  • 16 Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, 12713 Riyadh, Saudi Arabia.
  • 17 Institute of Human Genetics, Technical University München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
  • 18 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, 40225 Düsseldorf, Germany. Electronic address: [email protected].
PMID: 32004447 DOI: 10.1016/j.ajhg.2020.01.002
Abstract

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In LIGHT of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

Keywords

GARNL1; RalA signaling; TULIP1; West syndrome; epilepsy; muscular hypotonia; neurodevelopmental disorder.

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