A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.

TitleA reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.
Publication TypeJournal Article
Year of Publication2022
AuthorsMarafi, 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
JournalAm J Hum Genet
Date Published2022 Sep 01
KeywordsAnimals, Autoantibodies, Axons, Genomics, Humans, Intracellular Signaling Peptides and Proteins, Mammals, Mice, Myokymia, Nerve Tissue Proteins, Phenotype, Reverse Genetics

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.

Alternate JournalAm J Hum Genet
PubMed ID35948005
PubMed Central IDPMC9502070
Grant ListT32 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

Similar Publications

Chen F, Zhang Y, Chandrashekar DS, Varambally S, Creighton CJ. Global impact of somatic structural variation on the cancer proteome. Nat Commun. 2023;14(1):5637.
Rhie A, Nurk S, Cechova M, Hoyt SJ, Taylor DJ, Altemose N, et al.. The complete sequence of a human Y chromosome. Nature. 2023;621(7978):344-354.
Saengboonmee C, Sorin S, Sangkhamanon S, Chomphoo S, Indramanee S, Seubwai W, et al.. γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus. World J Gastroenterol. 2023;29(28):4416-4432.
Wojcik MH, Reuter CM, Marwaha S, Mahmoud M, Duyzend MH, Barseghyan H, et al.. Beyond the exome: What's next in diagnostic testing for Mendelian conditions. Am J Hum Genet. 2023;110(8):1229-1248.
Schlosser P, Zhang J, Liu H, Surapaneni AL, Rhee EP, Arking DE, et al.. Transcriptome- and proteome-wide association studies nominate determinants of kidney function and damage. Genome Biol. 2023;24(1):150.
Chin C-S, Behera S, Khalak A, Sedlazeck FJ, Sudmant PH, Wagner J, et al.. Multiscale analysis of pangenomes enables improved representation of genomic diversity for repetitive and clinically relevant genes. Nat Methods. 2023;20(8):1213-1221.
Harris RA, McAllister JM, Strauss JF. Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome. Int J Mol Sci. 2023;24(13).
Qian X, Srinivasan T, He J, Chen R. The Role of Ceramide in Inherited Retinal Disease Pathology. Adv Exp Med Biol. 2023;1415:303-307.
Lu J, Zheng KQ, Bertrand RElaine, Quinlan J, Ferdous S, Srinivasan T, et al.. Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model. Exp Eye Res. 2023;234:109596.
Calame DG, Guo T, Wang C, Garrett L, Jolly A, Dawood M, et al.. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease. Am J Hum Genet. 2023;110(8):1394-1413.