A Proteopathy Disease: Gaucher’s Disease Diane Lokou Chem 4700 – Protein Structure Dr. Michael...
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Transcript of A Proteopathy Disease: Gaucher’s Disease Diane Lokou Chem 4700 – Protein Structure Dr. Michael...
A Proteopathy Disease: Gaucher’s Disease
Diane LokouChem 4700 – Protein Structure
Dr. Michael KirbergerSpring 2015
Where does the name Gaucher come from?
• The disease obtained its name from its discoverer, Phillipe Charles Ernest Gaucher, a French physician in the 1800s when he discovered the disease. In 1882, he described for the first time the symptoms of a disease, later known as Gaucher Disease.
• Other names such as Gaucher splenomegaly, Glucosylceramide lipidosis, and Kerasin histiocytosis are used to name the disease.
Background of Gaucher’s Disease
Hereditary disease. The mutations occur in a single gene called GBA; these changes cause very
low levels of glucocerebrosidase
The recessive mutation is seen in males and females.
It is an autosomal recessive disorder of metabolism due to the lack of glucocerebrosidase also
known as acid β-glucosidase, a lysosomal enzyme which catalyzes glycolipid glucocerebroside
hydrolysis to ceramide and glucose.
Gaucher’s Disease results from the accumulation of fatty substances in cells and some organs
because of the deficiency of the enzyme, mainly in macrophages family or monocytes as the
macrophages fail to eliminate the waste product.
Glucosylceramide is a component of white and red blood cells’ membrane.
- In type 1, it accumulates in visceral organs (liver, spleen, bone marrow).
- In type 2 and 3, it accumulates in the central nervous system.
Statistics of Gaucher’s Disease
The disease is more frequent among people who are of Ashkenazi Jewish ancestry.
Occurrence in about 1 in 50,000 to 1 in 100,000 individuals in the general population.
Type 1 is present 1 in 500 to 1 in 1000 people of Ashkenazi Jewish ancestry
About 1 in 14 Ashkenazi Jews is a carrier.
Type 2 and Type 3 of the disease are not as common.
About 6,000 people in the United States are estimated to have the type 1 of Gaucher’s Disease.
Enzyme Description
Acid β-glucosidase is encoded by the gene GBA which is 7.6 kb long and located at 1q21 locus (long (q) arm of chromosome 1 at position 21).
GBA gene is located from base pair 155,234,447 to base pair 155,244,861 on chromosome 1.
GBA protein is 497 amino acids long with a molecular weight of 55.6KD.
GBA gene location
http://ghr.nlm.nih.gov/gene/GBA#location
Glucosidase, Beta, Acid
PyMOL Viewer
Beta strands and alpha-helices
Location of the mutations
Almost 200 mutations have been identified in Gaucher’s Disease;
these four changes are found in all 3 types:
L444P: major SNP (single nucleotide polymorphisms: single
nucleotide variations in the genome that occur at a frequency of
more than 1%) associated with GBA gene.
V460V
D409H
A456P
• SNPs occur around every 3000 base pairs in human genome.
• N370S, L444P, and R463C were the most common mutations
identified in preceding findings in 60 patients with types 1 and 3
of the disease.
• E326K mutation had also been identified in patients with all
three types, but in each case it was found on the same allele with
another GBA mutation.PyMOL Viewer
Symptoms of Gaucher’s Disease
Although the symptoms vary among people with this disorder, the common clinical symptoms are:
- Hepatosplenomegaly
- Anemia
- Thrombocytopenia
- Bone pain and fractures
Depending on the type of Gaucher disease, other symptoms are involved
Type 1 Gaucher disease:
• In addition to the major symptoms, there is also lung disease. This is the most common type and the
symptoms may appear earlier or in adulthood and the signs are so mild in many individuals that they do
not experience any problems from the disorder.
Type 2 and Type 3 Gaucher disease:
• In addition to the major symptoms, there are also nervous system symptoms such as eye problems,
seizures and brain damage.
• With type 2, the severe medical problems start in infancy and the individuals’ life span does not
usually exceed age two; some die during the newborn period, often with excessive fluid accumulation
or serious skin problems.
• With type 3, the symptoms may start before the age of two, but usually in a more slowly progressive
disease process and the degree of brain involvement is rather variable. The individuals typically have
slowing of their horizontal eye movements.
Diagnosis of Gaucher’s Disease
The diagnosis is based on clinical symptoms and laboratory testing.
A diagnosis based on clinical symptoms is supposed in individuals with:
• bone problems
• enlarged liver and spleen (hepatosplenomegaly)
• changes in red blood cell levels
• easy bleeding
• bruising from low platelets or signs of nervous system problems.
Diagnosis of Gaucher’s Disease
A diagnosis based on laboratory testing:
• A blood test is done to measure the activity level of the enzyme glucocerebrosidase; this enzyme has very low levels of activity in individuals who have the disease.
• Another type of laboratory testing is the GBA gene DNA analysis for the four most common GBA mutations.
• Enzyme and DNA testing can be done prenatally; bone marrow or liver biopsy is not essential to establish the diagnosis.
Treatments for Gaucher’s DiseaseEnzyme replacement therapy (ERT) is not an option for all patients with Gaucher disease. Symptoms in
type 1 individuals can be treated with available glucosylceramide synthase inhibitors like:
• Zavesca (miglustat) oral drug for adults.
• Genzyme’s Cerdelga (eliglustat) Capsules for long-term treatment for adults.
Enzyme replacement therapy:
• Cerezyme® (imiglucerase for injection) in 1994
• ELELYSO™ (taliglucerase alfa for injection), a hydrolytic lysosomal glucocerebroside-specific enzyme
for long-term ERT for adults with a confirmed diagnosis of Type 1. Approved by FDA on May 1, 2012.
• VPRIV® , a hydrolytic lysosomal glucocerebroside-specific enzyme for long-term enzyme replacement
therapy (ERT) for pediatric and adult patients with type 1
If ERT is not effective, some individuals may need surgery.
Splenectomy
Blood transfusions
Pain medications
Joint replacement surgery
Referenceshttp://ghr.nlm.nih.gov/gene/GBA#location
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410585.htm
http://www.gaucherdisease.org/gaucher-disease-treatments.php
www.genome.gov/25521505
PyMOL
www.protopage.com/gaucherdisease
http://www.medicinenet.com/gaucher_disease/
page8.htm#what_other_names_do_people_use_for_gaucher_disease
http://www.medicinenet.com/gaucher_disease/page3.htm
Manickam M, Ravanan P, Singh P, Talwar P. In silico identification of genetic variants in glucocerebrosidase
(GBA) gene involved in Gaucher's disease using multiple software tools. Frontiers In Genetics [serial online].
May 2014;5:1-10. Available from: Academic Search Complete, Ipswich, MA. Accessed March 14, 2015