Background: LAMP3 encodes a lysosomal membrane protein associated with lamellar bodies and has recently been proposed as a candidate gene for childhood interstitial lung diseases (chILD). Here, we identified two LAMP3 variants in a proband with chILD and performed functional validation of these variants as well as the previously reported variants to demonstrate the role of LAMP3 in pathology.
Methods: LAMP3 variants were identified by exome sequencing. Ex vivo studies included mRNA analysis from nasal brushing and lung tissue and immunohistochemistry from lung biopsy. In vitro functional analyses in the A549 cell line included immunofluorescence staining and expression analysis of LAMP3. Interactions between LAMP3 and the surfactant protein (SP)-B and SP-C were evaluated by co-immunoprecipitation.
Findings: Two heterozygous LAMP3 variants (Y302Qfs∗2 and T268M) were identified in a 15 year old boy with chILD. LAMP3 mRNA revealed that the frameshift variant resulted in nonsense-mediated mRNA decay. Reduced LAMP3 expression was confirmed in the patient's lung tissue. Functional studies of the T268M and the previously reported G288R variant revealed reduced levels of the mutant proteins. In addition, impaired N-glycosylation and protein instability were demonstrated with the T268M variant. Finally, we provided evidence for an interaction between LAMP3 and SP-B and SP-C, revealing a direct link between LAMP3 and surfactant metabolism.
Interpretation: LAMP3 bi-allelic variants leading to LAMP3 dysfunction emerges as a cause of chILD associated with a heterogeneous phenotype that remains to be further defined. The close links between LAMP3 and surfactant metabolism could explain the pathophysiology of this genetic disease.
Funding: No specific funding.
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Bi-allelic LAMP3 variants in childhood interstitial lung disease: a surfactant-related disease.
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Sorbonne University, Inserm UMR_S933 Laboratory of Childhood Genetic Diseases, Armand Trousseau Hospital, Paris, France; Assistance Publique Hôpitaux de Paris, Pediatric Pulmonology Department, Reference Centre for Rare Lung Diseases (RespiRare), Armand Trousseau Hospital, Paris, France.
Background: LAMP3 encodes a lysosomal membrane protein associated with lamellar bodies and has recently been proposed as a candidate gene for childhood interstitial lung diseases (chILD). Here, we identified two LAMP3 variants in a proband with chILD and performed functional validation of these variants as well as the previously reported variants to demonstrate the role of LAMP3 in pathology.
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From the Department of Human Genetics (K.M., E.Y., U.R., L.K., G.A.R., Z.G.-O.), Montreal Neurological Institute (K.M., E.Y., U.R., L.K., J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Department of Neurology and Neurosurgery (J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Centre de Recherche en Biologie Structurale (J.-F.T.), and Department of Pharmacology and Therapeutics (J.-F.T.), McGill University, Montréal, Quebec, Canada; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Paris Brain Institute and Sorbonne University, France; Oxford Parkinson's Disease Centre (OPDC) (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Center for Advanced Research in Sleep Medicine (J.Y.M., J.-F.G., A.D., R.B.P.), Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'Île-de-Montréal-Hôpital du Sacré-Coeur de Montréal; Departments of Psychiatry (J.Y.M.) and Neurosciences (A.D.), Université de Montréal; Department of Psychology (J.-F.G.), Université du Québec à Montréal, Canada; National Reference Center for Narcolepsy (Y.D.), Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Clinical Neurology Unit (G.L.G., M.V., F.J., A.B.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.) and Department of Medicine (DAME) (M.V.), University of Udine, Italy; Sleep Disorders Clinic (B.H., A.S., E.H.), Department of Neurology, Medical University of Innsbruck, Austria; Department of Neurology (K.S., D.K.) and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Neurology (W.O., A.J., F.S.-D.), Philipps University, Marburg, Germany; Department of Biomedical, Metabolic and Neural Sciences (G.P.), University of Modena and Reggio-Emilia; IRCCS (G.P.), Institute of Neurological Sciences of Bologna; Neurology Unit (E.A.), Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; Department of Medical Sciences and Public Health (M.F., M.P.), Sleep Disorder Research Center, University of Cagliari, Italy; Paracelsus-Elena-Klinik (B.M., C.T., F.S.-D.), Kassel; Department of Neurosurgery (B.M., C.T.), University Medical Centre Göttingen, Germany; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic; EuroMov Digital Health in Motion (V.C.D.C.), University of Montpellier IMT Mines Ales; University Lille North of France (C.C.M.), Department of Clinical Neurophysiology and Sleep Center, CHU Lille; Department of Sleep Medicine and Neuromuscular Disorders (A.H.), University of Müenster, Germany; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel; Department of Neurology (F.D.), University Hospital Antwerp, Edegem, Belgium; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; and Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN.
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