Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants

Abstract

Objective: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure.

Methods: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure.

Results: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly 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 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.

© 2021 American Academy of Neurology.

Figures

Figure 1. Families' Pedigrees

The pedigree structure of the 2 families (family I and family II); affected individuals are shown as filled symbols, on which complete sequencing analysis was performed and a pathogenic CHRNA3 genetic variant was found.

Figure 2. Valsalva Maneuver Tracings

Continuous heart rate (upper channel), blood pressure (middle channel), and pressure (third channel during Valsalva maneuver) in all affected individuals (I-4, I-5, II-3). Valsalva maneuver pressures were between 30 and 40 mm Hg in all 3 individuals.

Figure 3. Pharmacologic Testing

(A) Effect of 60 mg pyridostigmine on standing systolic blood pressure (SBP) and time in I-5. (B) I-3 and I-4 had a normal pressor response to tyramine, which indicated preserved sympathetic postganglionic neurons.

Figure 4. Ophthalmologic Evaluation

Ophthalmologic evaluation showed peripheral transillumination iris defects in I-5 with infrared image (A) and II-3 with standard clinical slit lamp (B).

Figure 5. Model of Nicotinic Acetylcholine Receptor (nACHR) α3β4 and D230 Variant Location

Structural effect of D230N mutation on nAChR pentameric channel. The 3.8 Ångstrom resolution cryo-EM structure (PDB code 6PV8) of the ligand-bound human α3β4 nicotinic acetylcholine receptor is shown. The α3 subunits are shown in green and the β4 subunits are blue. All transmembrane regions are gray. The location of the D230N variant is shown with red spheres to demonstrate its proximity to the intersubunit interfaces and to the ligand binding cleft. The inset shows as sticks the neighboring residues of the native aspartic acid, highlighted here in orange. The replacement of this buried negative charge with a neutral residue will change the electrostatics of the site, which is likely to lead to a change in the dynamics of the protein by altering the interaction with the nearby lysine residue K176. Finally, the negative value of the Rosetta thermodynamic calculation predicts a hyperstabilization of the system that could also affect channel function.