Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia

Am J Hum Genet. 2014 Mar 6;94(3):385-94. doi: 10.1016/j.ajhg.2014.01.018. Epub 2014 Feb 27.


Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1β1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Blood Platelets / metabolism
  • Child
  • Child, Preschool
  • Cyclic GMP / metabolism
  • Esophageal Achalasia / metabolism*
  • Female
  • Genotype
  • Guanylate Cyclase / genetics*
  • Guanylate Cyclase / physiology*
  • Homozygote
  • Humans
  • Male
  • Moyamoya Disease / metabolism*
  • Muscle, Smooth, Vascular / metabolism
  • Mutation
  • Nitric Oxide / chemistry*
  • Nitric Oxide / metabolism
  • Pedigree
  • Platelet Adhesiveness
  • Platelet Aggregation
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Soluble Guanylyl Cyclase
  • Young Adult


  • GUCY1A2 protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Nitric Oxide
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Cyclic GMP

Supplementary concepts

  • Moyamoya disease 1