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