1. A Germline Variant in the PANX1 Gene Has Reduced Channel Function and Is Associated with Multisystem Dysfunction*ā¦
- Author
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John J. Kelly, Kara L. Levine, Audrey Schroeder, Silvia Penuela, Qing Shao, Kristin Lindstrom, Dale W. Laird, Ruoyang Shi, Michael F. Jackson, Jane Juusola, and Jessica L. Esseltine
- Subjects
0301 basic medicine ,Proband ,Male ,medicine.medical_specialty ,Heterozygote ,Adolescent ,Hearing Loss, Sensorineural ,Mutant ,Mutation, Missense ,Nerve Tissue Proteins ,Biology ,Primary Ovarian Insufficiency ,Biochemistry ,Germline ,Connexins ,03 medical and health sciences ,Paracrine signalling ,Consanguinity ,0302 clinical medicine ,Adenosine Triphosphate ,Internal medicine ,Cell Line, Tumor ,medicine ,Missense mutation ,Animals ,Humans ,Abnormalities, Multiple ,Kyphosis ,Molecular Biology ,Exome sequencing ,Germ-Line Mutation ,Family Health ,HEK 293 cells ,Homozygote ,Molecular Bases of Disease ,Cell Biology ,Syndrome ,medicine.disease ,Pedigree ,030104 developmental biology ,Endocrinology ,HEK293 Cells ,Scoliosis ,Sensorineural hearing loss ,Female ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. 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.650GāA) 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."
- Published
- 2016