Title | A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Marafi, D, Kozar, N, Duan, R, Bradley, S, Yokochi, K, Mutairi, FAl, Saadi, NWaill, Whalen, S, Brunet, T, Kotzaeridou, U, Choukair, D, Keren, B, Nava, C, Kato, M, Arai, H, Froukh, T, Faqeih, EAli, AlAsmari, AM, Saleh, MM, Vairo, FPinto E, Pichurin, PN, Klee, EW, Schmitz, CT, Grochowski, CM, Mitani, T, Herman, I, Calame, DG, Fatih, JM, Du, H, Coban-Akdemir, Z, Pehlivan, D, Jhangiani, SN, Gibbs, RA, Miyatake, S, Matsumoto, N, Wagstaff, LJ, Posey, JE, Lupski, JR, Meijer, D, Wagner, M |
Journal | Am J Hum Genet |
Volume | 109 |
Issue | 9 |
Pagination | 1713-1723 |
Date Published | 2022 Sep 01 |
ISSN | 1537-6605 |
Keywords | Animals, Autoantibodies, Axons, Genomics, Humans, Intracellular Signaling Peptides and Proteins, Mammals, Mice, Myokymia, Nerve Tissue Proteins, Phenotype, Reverse Genetics |
Abstract | The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3. |
DOI | 10.1016/j.ajhg.2022.07.006 |
Alternate Journal | Am J Hum Genet |
PubMed ID | 35948005 |
PubMed Central ID | PMC9502070 |
Grant List | T32 GM007526 / GM / NIGMS NIH HHS / United States UM1 HG006542 / HG / NHGRI NIH HHS / United States R35 NS105078 / NS / NINDS NIH HHS / United States K08 HG008986 / HG / NHGRI NIH HHS / United States T32 NS043124 / NS / NINDS NIH HHS / United States R01 GM106373 / GM / NIGMS NIH HHS / United States U01 HG011758 / HG / NHGRI NIH HHS / United States BB/T00875X/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom BB/N015142/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom BB/M010996/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom |
A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.
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