title: A Germline Variant in the PANX1 Gene Has Reduced Channel Function and Is Associated with Multisystem Dysfunction.
abstract: Pannexin1 (PANX1) is probably best understood as an ATP release channel involved in paracrine signaling. Given its ubiquitous expression, PANX1 pathogenic variants would be expected to lead to disorders involving multiple organ systems. Using whole exome sequencing, we discovered the first patient with a homozygous PANX1 variant (c.650G→A) resulting in an arginine to histidine substitution at position 217 (p.Arg217His). The 17-year-old female has intellectual disability, sensorineural hearing loss requiring bilateral cochlear implants, skeletal defects, including kyphoscoliosis, and primary ovarian failure. Her consanguineous parents are each heterozygous for this variant but are not affected by the multiorgan syndromes noted in the proband. Expression of the p.Arg217His mutant in HeLa, N2A, HEK293T, and Ad293 cells revealed normal PANX1 glycosylation and cell surface trafficking. Dye uptake, ATP release, and electrophysiological measurements revealed p.Arg217His to be a loss-of-function variant. Co-expression of the mutant with wild-type PANX1 suggested the mutant was not dominant-negative to PANX1 channel function. Collectively, we demonstrate a PANX1 missense change associated with human disease in the first report of a "PANX1-related disorder."
authors.affiliation: Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: Qing
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, Arizona 85016.
authors.forename: Kristin
authors.initials: K
authors.lastname: Lindstrom
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba R3E 0Z3, Canada,; Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, Manitoba R3E 0Z3, Canada.
authors.forename: Ruoyang
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Kelly
authors.affiliation: Division of Genetics, University of Rochester Medical Center, Rochester, New York 14642.
authors.forename: Audrey
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: GeneDx, Gaithersburg, Maryland 20877.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Levine
authors.affiliation: Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Esseltine
authors.affiliation: Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Penuela
authors.affiliation: Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba R3E 0Z3, Canada,; Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, Manitoba R3E 0Z3, Canada.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jackson
authors.affiliation: Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario N6A 5C1, Canada. Electronic address: dale.laird@schulich.uwo.ca.
authors.forename: Dale W
authors.initials: DW
authors.lastname: Laird
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D045744:Cell Line, Tumor; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006367:HeLa Cells; D006319:Hearing Loss, Sensorineural / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007738:Kyphosis / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000473:pathology; D012600:Scoliosis / Q000473:pathology; D013577:Syndrome
chemical_list: D017630:Connexins; D009419:Nerve Tissue Proteins; C492764:PANX1 protein, human; D000255:Adenosine Triphosphate
keywords: ATP; cell biology; cell surface protein; development; pannexin