Clinical findings and structural analysis involving a patient with a novel KLHL15 variant |
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| Institution: | 1. Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, EX2 5DW, UK;2. Peninsula Medical School, Faculty of Health, University of Plymouth, UK;3. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7HE, UK;4. Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, RG1 5AN, UK;5. Genes Australia, 298 Gilchrist Ave, Herston QLD, 4006, Australia;1. Neuberg Centre for Genomic Medicine, Ahmedabad, 380059, Gujarat, India;2. Kids Neuro Clinic and Child Rehabilitation Center, Nagpur, Maharashtra, India;3. Kpond Children Super Specialty Hospital, Aurangabad, Maharashtra, India;4. Apollo Hospitals, Ahmedabad, India;5. Integrated Centre for Child Neurodevelopment, Aurangabad, Maharashtra, India;6. Nizam''s Institute of Medical Sciences, Hyderabad, India;7. MGM Medical College and Hospitals, Aurangabad, India;8. Christian Medical College and Hospital, Vellore, India;9. Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India;10. SMS Medical College, Jaipur, India;1. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 9112001, Israel;2. Department of Genetics, Hadassah Medical Organization, Jerusalem, 9112001, Israel;1. Montpellier University, Service de Génétique Clinique, Centre de Compétence Maladies Osseuses Constitutionnelles, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;2. Montpellier University, Department of Molecular Genetics and Cytogenomics, Rare and Autoinflammatory Diseases Unit, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;3. Montpellier University, Pediatric Endocrinology and Nephrology Unit, Rare Diseases Competence Center for Bone Mineral Disease and Skeletal Dysplasia, OSCAR Network, Montpellier University Hospital, Montpellier, France;4. Montpellier University, Département d’Imagerie Pédiatrique, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;5. Montpellier University, Département dOphtalmologie, Centre de Référence Maladies Sensorielles Génétiques, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;6. Montpellier University, Département de Dermatologie, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;7. Montpellier University, Service d’Onco-hématologie Pédiatrique, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;8. Montpellier University, Institute for Neurosciences of Montpellier, INSERM, Montpellier, France;1. Department of Neonatology, Anhui Provincial Children''s Hospital/Children''s Hospital Affiliated to Anhui Medical University, Hefei, China;2. Department of Radiology, Anhui Provincial Children''s Hospital, Hefei, China;3. School of Basic Medical Sciences, Anhui Medical University, Hefei, China;4. School of Life Sciences, University of Science and Technology of China, Hefei, China;5. Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China;1. Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey;2. Department of Obstetrics and Gynecology, Division of Perinatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey;3. University of Groningen, University Medical Centre Groningen, Dept Genetics, Groningen, Netherlands;1. VASCERN PPL European Reference Centre: Expert Center for Lymphovascular Medicine, Nij Smellinghe Hospital, Drachten, the Netherlands;2. VASCERN PPL European Reference Centre: French Reference Center Rare Vascular Diseases, Department of Lymphology, AP-HP, HEGP Hôpital Européen Georges Pompidou, Paris, France;4. SW Thames Centre for Genomics, St George''s University Hospitals NHS Foundation Trust, UK and St George''s University of London, London, UK |
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| Abstract: | A de novo novel variant of uncertain significance p. (Arg532del) in the KLHL15 gene was identified by trio exome analysis in a child with global developmental delay, coarse facial features, repetitive behaviour, increased fatigability, poor feeding and gastro-oesophageal reflux. Comparative modelling and structural analysis were performed to gain insight into the effects of the variant on KLHL15 protein structure and function, with a view to aiding variant classification. The p. (Arg532del) variant affects a highly conserved residue within one of the Kelch repeats of the KLHL15 protein. This residue contributes to the stability of loop regions at the substrate binding surface of the protein; comparative modelling of the variant protein predicts altered topology at this surface, including at residue Tyr552, which is known to be important for substrate binding. We propose that it is highly probable that the p. (Arg532del) variant has a deleterious impact on KLHL15 structure, leading to a reduced level of protein function in vivo. |
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| Keywords: | KLHL15 Structural analysis Protein function Variant classification |
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