Data from: Neural pathways of autonomic reflexes in familial autonomic ganglionopathy

Objective: We determined the molecular basis of a new monogenetic recessive disorder that results in familial neurogenic orthostatic hypotension (nOH) with impaired sympathetic (SNS) and parasympathetic (PNS) activity.

Methods: Two adult siblings from one family (I-4, I-5) and an another subject from a second family (II-3) presented with severe nOH, poor compensatory increase in heart rate, small non-reactive pupils and constipation. All three affected members had low norepinephrine levels and diffuse autonomic failure.

Results: Whole exome sequencing of DNAs from subjects (I-4, I-5) showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115) /c.688G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, alpha 3 subunit (CHRNA3) gene. The II-3 from the second family was homozygous for the same frameshift(fs) variant (p.L303Dfs*115// p.L303Dfs*115). The CHRNA3 is a subunit of nicotinic acetylcholine receptors (nAChRs) that regulate SNS and PNS activity through fast synaptic transmission in the autonomic ganglia. The fs variant is obviously pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex.

Conclusions: We report a novel genetic disease that affected three individuals from two unrelated families who presented with nOH and diffuse autonomic failure. These subjects had rare pathologic variants in the CHRNA3 gene that co-segregate with and are predicted to be the likely cause of their SNS and PNS failure.