Instituto Valenciano de Microbiología
(IVAMI)

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
Email: 
www.ivami.com
CIF B-96337217

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Congenital defect of the bile acid synthesis types 1 and 2 (Congenital bile acid synthesis defect types 1 and 2) - Genes and AKR1D1 HSD3B7.

The congenital defect of the bile acid synthesis is a disorder characterized by cholestasis, an alteration affecting the production and release of bile liver cells. Bile during digestion is used to absorb fats and fat - soluble vitamins, such as vitamins A, D, E, and K. Those affected can not synthesize bile acids and produce an abnormal form of bile.

Signs and symptoms of congenital defect of the bile acid synthesis are developed frequently during the first weeks of life, but can start at any time from infancy to adulthood. Children usually growth retardation and jaundice due to altered bile flow and an accumulation of partially formed bile. An additional feature of the disease is steatorrhea. As the disease progresses, affected individuals may develop liver disorders including cirrhosis and hepatomegaly. Other signs and symptoms may include splenomegaly and inability to absorb certain fat - soluble vitamins, vitamin D, in particular, which can lead to rickets in some individuals. If left untreated, this disease can lead to cirrhosis and death in childhood.

The congenital defect of the bile acid synthesis is due to mutations in genes HSD3B7 and AKR1D1.

The HSD3B7 gene, located on the short arm of chromosome 16 (16p11.2), encoding the enzyme beta-hydroxysteroid dehydrogenase type-7-3 (3?-hsD7), found in liver cells. This enzyme is embedded in the membrane of the endoplasmic reticulum, involved in the processing and distribution of proteins. 3?-hsD7 enzyme involved in the production of bile acids which stimulate bile flow and help absorb fats and fat soluble vitamins. Bile acids are produced from cholesterol by multistep process. 3?-hsD7 enzyme is responsible for the second step in the process, which converts 7alpha- (?) -hydroxycholesterol in 7?-hydroxy-4-cholesten-3-1. Found at least 17 mutations in the gene responsible for congenital defect HSD3B7 of bile acid synthesis type 1. Most of these genetic mutations remove one or two base pairs of the gene or replacing amino acids in the enzyme. These mutations lead to coding a 3?-hsD7 enzyme with little or no function. Without sufficient functional enzyme 3?-hsD7, conversion of 7?-hydroxycholesterol to 7?-hydroxy-4-cholesten-3-one altered. 7?-hydroxycholesterol in its place becomes abnormal bile acid compounds which can not be transported outside the liver in the intestine, where the bile acids are required to absorb fats and fat soluble vitamins. This decrease in the production and release of bile acids generates cholestasis. As a result, abnormal cholesterol and bile acids accumulate in liver and fat soluble vitamins are not absorbed, causing the signs and symptoms of congenital defect of the bile acid synthesis type 1.

The AKR1D1 gene, located on the long arm of chromosome 7 (7q32-q33), encoding an enzyme called 4-3-oxo-5-? steroid dehydrogenase, found in liver cells. This enzyme is involved in the production of bile acids which stimulate bile flow and help absorb fats and fat soluble vitamins. Bile acids are produced from cholesterol by multistep process. The enzyme 3-oxo-5?-steroid dehydrogenase 4 is responsible for the third stage in the process, which converts 7-alpha (?) -hydroxy-4-cholesten-3-one 7-?-hydroxy-5? -colesten-3-1. They have identified more than 10 mutations in the gene responsible for congenital defect AKR1D1 of bile acid synthesis type 2. Most of these mutations replacing individual amino acids in the enzyme, which leads to the production of an enzyme-oxo 03.04 dehydrogenase -5-?-steroid with a strongly reduced function. Without sufficient functional enzyme, the conversion of 7?-hydroxy-4-cholesten-3-one 7?-hydroxy-5?-cholesten-3-one deteriorates. 7-?-hydroxy-4-cholesten-3-one becomes abnormal bile acid compounds which can not be transported outside the liver in the intestine, where the bile acids are needed to digest fat. This decrease in the production and release of bile acids leads to cholestasis. As a result, abnormal cholesterol and bile acids accumulate in liver and fat - soluble vitamins are not absorbed, leading to the signs and symptoms of congenital defect of the bile acid synthesis type 2.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with congenital defect of the bile acid synthesis by the complete PCR amplification of the exons of HSD3B7 and AKR1D1 genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).