Abstract P176: Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants. Novel Genetic Cause of Neurogenic Orthostatic Hypotension

Abstract

Patients with autonomic failure developed severe neurogenic orthostatic hypotension (nOH). There are only two reported genetic conditions that cause nOH, dopamine β-hydroxylase deficiency, and CYB561 deficiency; both affect norepinephrine synthesis resulting in an isolated sympathetic failure. Objective: To determine molecular basis of a new Mendelian cause of familial nOH with impaired cardiovagal function, and miosis associated with sympathetic (SNS) and parasympathetic (PNS) failure. Method and Results: The proband developed disabling nOH with poor compensatory increase in heart rate at 39 yrs of age. Plasma norepinephrine levels were abnormally low. His sister had onset of nOH in her late teens. Their parents and brother were healthy. Whole exome sequencing of DNAs from the proband and his affected sister showed that both were compound heterozygotes for c.907_908delCT (p.L303Dfs*115) /c.688G>A (p.D230N) variants in the acetylcholine receptor, neuronal nicotinic, alpha 3 subunit (CHRNA3) gene. CHRNA3 is a subunit of nicotinic acetylcholine receptors (nAChRs) that regulates blood pressure through modulation of synaptic transmission in the autonomic ganglia. The autonomic ganglia regulates both SNS and PNS activity. The frameshift (fs) and missense CHRNA3 variants were inherited from the sibs’ mother and father, respectively, and their non-affected brother was a nl/p.D230N heterozygote. The fs variant is obviously pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). Furthermore, we predict from structural modeling that the p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits and that it would destabilize the nAChR pentameric complex. In humans, the presence of acquired nAChR autoantibodies against the alpha 3 subunit is associated with nOH and non-reactive pupils. Conclusions: We report sibs affected with NOH and miosis who are compound heterozygotes forCHRNA3 variants that co-segregate with and have predicted effects on nAChR structure that suggest they likely cause this family’s SNS and PNS failure.