This negative feedback regulates the levels and expression of these circadian clock components.Without proper phosphorylation of hPER2 in the instance of a mutation in the CK1 binding site, less Per2 mRNA is transcribed and the period is shortened to less than 24 hours. Individuals with a shortened period due to this phosphorylation disruption entrain to a 24h light-dark cycle, which may lead to a phase advance, causing earlier sleep and wake patterns. However, a 22h period does not necessitate a phase shift, but a shift can be predicted depending on the time the subject is exposed to the stimulus, visualized on a Phase Response Curve (PRC). This is consistent with studies of the role of CK1ɛ (a unique member of the CK1 family) in the TTFL in mammals and more studies have been conducted looking at specific regions of the Per2 transcript. In 2005, Fus and Ptáčeks labs reported discovery of a mutation in CKIδ (a functionally redundant form of CK1ɛ in the phosphorylation process of PER2) also causing FASPS. An A-to-G missense mutation resulted in a threonine-to-alanine alteration in the protein. This mutation prevented the proper phosphorylation of PER2. The evidence for both a mutation in the binding domain of PER2 and a mutation in CKIδ as causes of FASPS is strengthened by the lack of the FASPS phenotype in wild type individuals and by the observed change in the circadian phenotype of these mutant individuals in vitro and an absence of said mutations in all tested control subjects.
Vanishing bile duct syndrome is a loose collection of diseases which leads to the injury to hepatic bile ducts and eventual ductopenia. Signs and symptoms
The presentation is dependent upon the underlying cause. The course can be rapid or chronic. Fatigue
Anorexia
Abdominal pain
Weight loss
Pruritus
Hyperlipidemia
Malabsorption
Fat-soluble vitamin deficiencies
Elevated alkaline phosphatase
Elevated gamma-glutamyltransferase
Elevated conjugated bilirubin

Cause
Congenital
In fetal and neonatal life the ductal plates are remodeled. The malformations can be atretic or fibrocystic. Atretic causes
Intrahepatic bile duct atresia (Alagille syndrome) (ALGS2 MIM:610205 and ALGS1 MIM:118450)
Extrahepatic bile duct atresia

Fibrocystic causes
Autosomal recessive polycystic kidney disease
Congential hepatic fibrosis
Carolis disease
Von Meyenburg complex

Chromosomal associations
Trisomy 17, 18 and 21

Genetic associations
Cystic fibrosis
Alpha 1 antitrypsin deficiency
Trihydroxycoprostanic acidemia
Bylers disease

Immunologic associations
Bile duct injury and loss can result from autoimmune destruction. T cells recognize biliary epithelial cell antigens causing injury and eventual atresia. Other causes
Primary biliary cirrhosis
Primary sclerosing cholangitis
Hodgkins lymphoma
Chronic graft-versus-host disease
Drugs(chlorpromazine)/Toxins
Ischemia

Diagnosis
Treatment
Treatment is dependent upon the underlying cause. Treatment is supportive as it is not possible to induce regrowth of lost ducts. Medical therapies
Ursodeoxycholic acid
Immunosuppression
General consensus is that more studies are needed before this can be considered
Organ transplant

References
External links
Uptodate:Hepatic ductopenia and vanishing bile duct syndrome