TY - JOUR
T1 - A reverse genetics and genomics approach to gene paralog function and disease
T2 - Myokymia and the juxtaparanode
AU - Marafi, Dana
AU - Kozar, Nina
AU - Duan, Ruizhi
AU - Bradley, Stephen
AU - Yokochi, Kenji
AU - Al Mutairi, Fuad
AU - Saadi, Nebal Waill
AU - Whalen, Sandra
AU - Brunet, Theresa
AU - Kotzaeridou, Urania
AU - Choukair, Daniela
AU - Keren, Boris
AU - Nava, Caroline
AU - Kato, Mitsuhiro
AU - Arai, Hiroshi
AU - Froukh, Tawfiq
AU - Faqeih, Eissa Ali
AU - AlAsmari, Ali M.
AU - Saleh, Mohammed M.
AU - Pinto e Vairo, Filippo
AU - Pichurin, Pavel N.
AU - Klee, Eric W.
AU - Schmitz, Christopher T.
AU - Grochowski, Christopher M.
AU - Mitani, Tadahiro
AU - Herman, Isabella
AU - Calame, Daniel G.
AU - Fatih, Jawid M.
AU - Du, Haowei
AU - Coban-Akdemir, Zeynep
AU - Pehlivan, Davut
AU - Jhangiani, Shalini N.
AU - Gibbs, Richard A.
AU - Miyatake, Satoko
AU - Matsumoto, Naomichi
AU - Wagstaff, Laura J.
AU - Posey, Jennifer E.
AU - Lupski, James R.
AU - Meijer, Dies
AU - Wagner, Matias
N1 - Publisher Copyright:
© 2022
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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.
AB - 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.
KW - KCNA
KW - LGI3
KW - bi-allelic variation
KW - facial myokymia
KW - gene and genome instability
KW - genomic rearrangement
KW - multi-exonic CNV
KW - neurobiology of disease
KW - peripheral nerve hyperexcitability syndromes
KW - potassium channel complexes
UR - http://www.scopus.com/inward/record.url?scp=85136676052&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85136676052&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2022.07.006
DO - 10.1016/j.ajhg.2022.07.006
M3 - Article
C2 - 35948005
AN - SCOPUS:85136676052
SN - 0002-9297
VL - 109
SP - 1713
EP - 1723
JO - American journal of human genetics
JF - American journal of human genetics
IS - 9
ER -