The endoplasmic reticulum (ER) quality control processes recognize and remove 
aberrant proteins from the secretory pathway. Several variants of the plasma 
protein fibrinogen are recognized as aberrant and degraded by ER-associated 
protein degradation (ERAD), thus leading to hypofibrinogenemia. A subset of 
patients with hypofibrinogenemia exhibit hepatic ER accumulation of the variant 
fibrinogens and develop liver cirrhosis. One such variant named Aguadilla has a 
substitution of Arg375 to Trp in the gamma-chain. To understand the cellular 
mechanisms behind clearance of the aberrant Aguadilla gamma-chain, we expressed 
the mutant gammaD domain in yeast and found that it was cleared from the ER via 
ERAD. In addition, we discovered that when ERAD was saturated, aggregated 
Aguadilla gammaD accumulated within the ER while a soluble form of the 
polypeptide transited the secretory pathway to the trans-Golgi network where it 
was targeted to the vacuole for degradation. Examination of Aguadilla gammaD in 
an autophagy-deficient yeast strain showed stabilization of the aggregated ER 
form, indicating that these aggregates are normally cleared from the ER via the 
autophagic pathway. These findings have clinical relevance in the understanding 
of and treatment for ER storage diseases.