Pathogenic variants of ADAM22 affecting either its biosynthesis and/or its interactions with either LGI1 and/or PSD-95 have been recently identified in individuals with developmental and epileptic encephalopathy. Here, we describe a girl with seizures, delayed psychomotor development, and behavioural disorder, carrying a homozygous variant in ADAM22 (NM_021723.5:c.2714C > T). The variant has a surprisingly high frequency in the Roma population of the Czech and Slovak Republic, with 11 of 213 (∼5.2%) healthy Roma individuals identified as heterozygous carriers. Structural in silico characterization revealed that the genetic variant encodes the missense variant p.S905F, which localizes to the PDZ-binding motif of ADAM22. Studies in transiently transfected mammalian cells revealed that the variant has no effect on biosynthesis and stability of ADAM22. Rather, protein-protein interaction studies showed that the p.S905F variant specifically impairs ADAM22 binding to PSD-95 and other proteins from a family of membrane-associated guanylate kinases, while it has only minor effect on ADAM22-LGI1 interaction. Our study indicates that a significant proportion of epilepsy in patients of Roma ancestry may be caused by homozygous c.2714C > T variants in ADAM22. The study of this ADAM22 variant highlights a novel pathogenic mechanism of ADAM22 dysfunction and reconfirms an essential role of interaction of ADAM22 with membrane-associated guanylate kinases in seizure protection in humans.

Children's Faculty Hospital Košice 040 11 Slovakia

Department of Paediatric and Adolescent Medicine Faculty of Medicine P J Šafárik University Košice 040 01 Slovak Republic

Department of Physiological Sciences School of Life Science SOKENDAI Okazaki 444 8585 Japan

Division of Membrane Physiology Department of Molecular and Cellular Physiology National Institute for Physiological Sciences National Institutes of Natural Sciences Okazaki 444 8787 Japan

Division of Molecular and Cellular Pharmacology Nagoya University Graduate School of Medicine Nagoya 466 8550 Japan

Division of Neuropharmacology Nagoya University Graduate School of Medicine Nagoya 466 8550 Japan

Medical Genetics Outpatient Service Unilabs Slovakia Ltd Košice 040 01 Slovakia

Research Unit for Rare Diseases Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague 128 08 Prague 2 Czech Republic

Zobrazit více v PubMed

Fukata  Y, Adesnik  H, Iwanaga  T, Bredt  DS, Nicoll  RA, Fukata  M. Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science. 2006;313(5794):1792–1795. PubMed

Fukata  Y, Hirano  Y, Miyazaki  Y, Yokoi  N, Fukata  M. Trans-synaptic LGI1-ADAM22-MAGUK in AMPA and NMDA receptor regulation. Neuropharmacology. 2021;194:108628. PubMed

Ogawa  Y, Oses-Prieto  J, Kim  MY, et al.  ADAM22, A Kv1 channel-interacting protein, recruits membrane-associated guanylate kinases to juxtaparanodes of myelinated axons. J Neurosci. 2010;30(3):1038–1048. PubMed PMC

Ozkaynak  E, Abello  G, Jaegle  M, et al.  Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling. J Neurosci. 2010;30(10):3857–3864. PubMed PMC

Liu  H, Shim  AH, He  X. Structural characterization of the ectodomain of a disintegrin and metalloproteinase-22 (ADAM22), a neural adhesion receptor instead of metalloproteinase: Insights on ADAM function. J Biol Chem. 2009;284(42):29077–29086. PubMed PMC

Fukata  Y, Yokoi  N, Miyazaki  Y, Fukata  M. The LGI1-ADAM22 protein complex in synaptic transmission and synaptic disorders. Neurosci Res. 2017;116:39–45. PubMed

Yamagata  A, Miyazaki  Y, Yokoi  N, et al.  Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22. Nat Commun. 2018;9(1):1546. PubMed PMC

Fukata  Y, Chen  X, Chiken  S, et al.  LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention. Proc Natl Acad Sci U S A. 2021;118(3):e2022580118. PubMed PMC

Lovero  KL, Fukata  Y, Granger  AJ, Fukata  M, Nicoll  RA. The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function. Proc Natl Acad Sci U S A. 2015;112(30):E4129–E4137. PubMed PMC

Chen  X, Fukata  Y, Fukata  M, Nicoll  RA. MAGUKs are essential, but redundant, in long-term potentiation. Proc Natl Acad Sci U S A. 2021;118(28):e2107585118. PubMed PMC

Sagane  K, Hayakawa  K, Kai  J, et al.  Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci. 2005;6:33. PubMed PMC

Fukata  Y, Lovero  KL, Iwanaga  T, et al.  Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A. 2010;107(8):3799–3804. PubMed PMC

Kalachikov  S, Evgrafov  O, Ross  B, et al.  Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet. 2002;30(3):335–341. PubMed PMC

Muona  M, Fukata  Y, Anttonen  AK, et al.  Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy. Neurol Genet. 2016;2(1):e46. PubMed PMC

Maddirevula  S, Alzahrani  F, Al-Owain  M, et al.  Autozygome and high throughput confirmation of disease genes candidacy. Genet Med. 2019;21(3):736–742. PubMed PMC

van der Knoop  MM, Maroofian  R, Fukata  Y, et al.  Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy. Brain. 2022;145(7):2301–2312. PubMed PMC

McKenna  A, Hanna  M, Banks  E, et al.  The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297–1303. PubMed PMC

Paila  U, Chapman  BA, Kirchner  R, Quinlan  AR. GEMINI: Integrative exploration of genetic variation and genome annotations. PLoS Comput Biol. 2013;9(7):e1003153. PubMed PMC

Yokoi  N, Fukata  Y, Kase  D, et al.  Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy. Nat Med. 2015;21(1):19–26. PubMed

Mishra  S, Rai  A, Srivastava  P, Phadke  SR. A mild phenotype of LGI4-related arthrogryposis multiplex congenita with intrafamilial variability. Eur J Med Genet. 2020;63(3):103756. PubMed

Xue  S, Maluenda  J, Marguet  F, et al.  Loss-of-function mutations in LGI4, a secreted ligand involved in Schwann cell myelination, are responsible for arthrogryposis multiplex congenita. Am J Hum Genet. 2017;100(4):659–665. PubMed PMC

Bermingham  JR, Shearin  H, Pennington  J, et al.  The claw paw mutation reveals a role for Lgi4 in peripheral nerve development. Nat Neurosci. 2006;9(1):76–84. PubMed

Kegel  L, Jaegle  M, Driegen  S, et al.  Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination. Development. 2014;141(8):1749–1756. PubMed

Nishino  J, Saunders  TL, Sagane  K, Morrison  SJ. Lgi4 promotes the proliferation and differentiation of glial lineage cells throughout the developing peripheral nervous system. J Neurosci. 2010;30(45):15228–15240. PubMed PMC

Yokoi  N, Fukata  Y, Okatsu  K, et al.  14-3-3 proteins stabilize LGI1-ADAM22 levels to regulate seizure thresholds in mice. Cell Rep. 2021;37(11):110107. PubMed