Transcript A Proteopathie Disease - Clayton State University

A Proteopathy Disease: Gaucher’s Disease
Diane Lokou
Chem 4700 – Protein Structure
Dr. Michael Kirberger
Spring 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
Beta strands and
alpha-helices
PyMOL Viewer
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.
PyMOL Viewer
• 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.
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 Disease
Enzyme 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
References
http://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_dis
ease
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