Sitosterolemia is a rare autosomal recessive genetic disorder caused by mutations in the ABCG5 or ABCG8 genes, which code for the sterolin protein. This leads to an inability to eliminate dietary plant sterols from the body, resulting in their accumulation and deposition in tissues. Symptoms include premature atherosclerosis, fatty deposits under the skin called xanthomas, and blood abnormalities. Treatment focuses on a strictly plant sterol-restricted diet, cholesterol-lowering medications, and potentially bile acid sequestrants.

1. ISAC SUGANCE
Sitosterolemia

2. Sitosterolemia
Sitosterolemia is a autosomal recessive condition caused by mutations in
the ABCG5 or ABCG8 gene. These genes provide instructions for making
the two halves of a protein called sterolin. This protein is involved in
eliminating plant sterols, which cannot be used by human cells.

3. Alternative Names
 beta-sitosterolemia
 phytosterolemia
 plant sterol storage disease

4. Frequency
 Only 80 to 100 individuals with sitosterolemia have been described in
the medical literature. However, researchers believe that this condition
is likely underdiagnosed because mild cases often do not come to
medical attention. Studies suggest that the prevalence may be at least 1
in 50,000 people

7. Expression
 Germ Layers: ectoderm endoderm mesoderm
 Systems: cardiovascular digestive integumentary lymphatic skeleton
 Regions: Head and neck: ear.
Thorax: heart.
Abdomen: duodenum, intestine, liver, small intestine,
spleen.
Limb: ankle, digit, elbow, finger, foot, hand, hip,
knee, lower limb, shoulder, toe, upper limb,
wrist.
General: blood, blood vessel, coagulation system, red
blood cell, skin.

8. ABCG5 gene & ABCG8 gene

9. Gene expression
 Molecular level - The ABCG5 gene provides instructions for making
sterolin-1, which makes up half of a protein called sterolin. The other half
of the sterolin protein, sterolin-2, is produced from a gene called ABCG8.
 Cellular level - Sterolin is a transporter protein, which is a type of
protein that moves substances across cell membranes. It is found mostly in
cells of the intestines and liver and transports plant sterols.
 Organism level - After plant sterols are absorbed from food into
intestinal cells, the sterolin transporters in these cells pump them back
into the intestinal tract. Sterolin transporters in liver cells pump the plant
sterols into a fluid called bile that is released into the intestine.

10. Expression of the gene (2)
 In which tissues is expressed?
Expressed in a tissue-specific manner in the liver, intestine, and
gallbladder.
 Produced protein - Sterolin
 Place of processing of the protein – Rough endoplasmic
reticulum
 Location of the protein in the cell – Nucleus, Plasma
membrane.

11. Genetics
 Type of inheritance : Autosomal Recessive
 Genotypes of affected people : aa
 Genotypes of Carrier people : Aa
 Expressivity : Variable expressivity
 Penetrance : Incomplete (1 in 50,000 people.)
 Pleiotropy : Nil
 Genetic Heterogeneity : Mutations of both genes ABCG5 and ABCG8
causes Sitosteolemia

12.  Paraclinical : A blood test that reveals frank elevation in phytosterol
levels is considered diagnostic for sitosterolemia.
 Molecular Test : Genetic testing for mutations in the ABCG8 and
ABCG5 genes is available to confirm the diagnosis.
 Marker : Plasma concentrations of sitosterol above 1 mg/dL are
considered to be diagnostic of sitosterolemia

14. Functions of the protein
 Function of the protein - Sterolin is involved in eliminating plant sterols,
which are fatty components of plant-based foods that cannot be used by human
cells.
 Processes in which is involved - From the intestine, the plant sterols are
eliminated with the feces. This process removes most of the dietary plant sterols,
and allows only about 5 percent of these substances to get into the bloodstream.
Sterolin also helps regulate levels of cholesterol, another fatty substance found in
animal products, in a similar fashion; normally about 50 percent of cholesterol in
the diet is absorbed by the body.
 Interaction with other proteins – Binary interaction with Cytoplasmic
Protein nck1_human

15. Mutations and their consequences
 Known mutations – one (missense mutations)
 Consequences – Sitosterolemia
Modifications in metabolism determined by abnormal / missing protein –
 (Molecular level) Mutations in either ABCG5 (G5) or ABCG8 (G8) cause
sitosterolemia, an autosomal recessive disorder leads to hypo-production of Protein
sterolin
 (cellular level) characterized by the accumulation of both plant-derived
(primarily sitosterol) and animal-derived sterols (cholesterol) in plasma and tissues .
 (Organism level) G5 and G8 are located on the apical surfaces of enterocytes and
hepatocytes, where they limit the absorption of dietary sterols and promote the
excretion of cholesterol into bile, respectively. Individuals with sitosterolemia have a
generalized increase in the absorption of dietary neutral sterols and a defect in the
excretion of these sterols into bile. This impairment in sterol trafficking results in
the deposition of neutral sterols in the skin as xanthomas and in the walls of the
coronary arteries, causing premature atherosclerosis.

16. Primary manifestations
 Signs and symptoms of sitosterolemia may begin to appear early in life
after foods containing plant sterols are introduced into the diet,
although some affected individuals have no obvious symptoms.
 In people with sitosterolemia, accumulation of fatty deposits in arteries
(atherosclerosis) can occur as early as childhood. These deposits narrow
the arteries and can eventually block blood flow, increasing the chance
of a heart attack, stroke, or sudden death.

17. Xanthomas (manifestation)
 Some people with sitosterolemia develop small yellowish growths called
xanthomas beginning in childhood. Xanthomas consist of accumulated
lipids and may be located anywhere on or just under the skin, typically
on the heels, knees, elbows, and buttocks. They may also occur in the
bands that connect muscles to bones (tendons), including tendons of
the hand and the tendon that connects the heel of the foot to the calf
muscles (the Achilles tendon). Large xanthomas can cause pain,
difficulty with movement, and cosmetic problems.

18. Complications (blood)
 Joint stiffness and pain resulting from plant sterol deposits may also
occur in individuals with sitosterolemia. Less often, affected individuals
have blood abnormalities. Occasionally the blood abnormalities are the
only signs of the disorder. The red blood cells may be broken down
(undergo hemolysis) prematurely, resulting in a shortage of red blood
cells (anemia). This type of anemia is called hemolytic anemia. Affected
individuals sometimes have abnormally shaped red blood cells called
stomatocytes. In addition, the blood cell fragments involved in clotting,
called platelets or thrombocytes, may be abnormally large
(macrothrombocytopenia).

19. Treatment
 The disorder is treated by strictly reducing the intake of foods rich in plant sterols (e.g.,
vegetable oils, olives and avocados). However, dietary therapy is often never fully sufficient
to control this disease since plant sterols are constituents of all plant-based foods. Statins
have been used, and while these lower cholesterol levels and may ameliorate atherosclerotic
disease, plant sterol levels are insufficiently lowered by their use alone. (PRIMARY
PROPHYLAXIS to reduce SEVERITY)
 If dietary treatment alone is insufficient, bile acid-binding resins (8-15 g/d) (e.g.,
cholestyramine, colestipol) could be considered. In October 2002, a new cholesterol
absorption inhibitor, ezetimibe(10 mg/day), received US Food and Drug Administration
(FDA) approval for use in sitosterolemia. This drug is now the standard of care, as it blocks
sterol entry and can be used in combination with bile-acid resins.
 Finally, bypass has been performed in select cases to decrease the levels of plant sterols in
the body, though this therapy was undertaken prior to the advent of ezetimibe.

21. Bibliography / webography
 https://www.genecards.org/cgi-bin/carddisp.pl?gene=ABCG8
 https://www.genecards.org/cgi-
bin/carddisp.pl?gene=ABCG5&keywords=ABCG5
 https://www.uniprot.org/uniprot/Q9H222#function
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785388/
 https://ghr.nlm.nih.gov/gene/ABCG8
 https://ghr.nlm.nih.gov/gene/ABCG5