ALMS1

Alstrom syndrome 1 also known as ALMS1 is a protein which in humans is encoded by the ''ALMS1'' gene.

Gene

The gene is located on the short arm of chromosome 2 (2p13.2) on the plus (Watson) strand. It is 224,161 bases in length organised into 23 exons. The encoded protein has 4,167 amino acids and molecular weight of 460,937 Da. Three isoforms are known. Mutations associated with disease are usually found in exons 8, 10 and 16.

Tissue and subcellular distribution

The gene is expressed in fetal tissues including the aorta, brain, eye, kidney, liver, lung, olfactory bulb, pancreas, skeletal muscle, spleen and testis. The protein is found in the cytoplasm, centrosome, cell projections and cilium basal body. During mitosis it localizes to both spindle poles.

Structure

The protein has a large tandem-repeat domain comprising 34 imperfect repetitions of 47 amino acids as well as additional low complexity regions.

Function

The encoded protein functions in microtubule organization, particularly in the formation and maintenance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. rovided by RefSeq, Apr 2014

Disease association

Mutations in the ''ALMS1'' gene have been found to be causative for Alström syndrome with a total of 81 disease-causing mutations.

Multiple mutations are known: the current (2007) total is 79. These include both nonsense and frameshift mutations. Most of the mutations have been found in exons 8,10 and 16.

Knockdown of ''Alms1'' by short interfering RNA in mouse inner medullary collecting duct cells caused defective ciliogenesis. Cilia were stunted and treated cells lacked the ability to increase calcium influx in response to mechanical stimuli.

Organ systems

Primary cilia are hair-like projections that are on the surface of many cell types. ALMS1 is localized to the basal body of cilia and will help regulate signaling pathways all over the body. When there is a mutation in the ALMS1, the primary cilia will become dysfunctional. This will affect many pathways in the body due to this mutation. The Endocrine system is affected by a mutation in ALMS1 by having symptoms of early-onset obesity, insulin resistance, and type 2 diabetes. When looking at the cardiovascular system there is a symptom of dilated cardiomyopathy, which can lead to heart failure. In the sensory system, there is a disease called cone-rod dystrophy that takes place because of ALMS1 which can cause loss of hearing and vision. With the renal system, the mutation can cause progressive kidney dysfunction which can lead to end-stage renal disease. Lastly, the hepatic system can be affected by fatty liver disease. The mutation will cause different kinds of reactions in the organ systems.

Kidney damage

ALMS1 has a very critical role in maintaining renal function and blood pressure homeostasis. It is hypothesized that a mutation in ALMS1 in macula densa cells will amplify tubuloglomerular feedback (TGF) and cause some problems in the kidneys due to an overreaction to sodium changes. The TGF mechanism will then reduce the glomerular filtration rate (GFR). This can lead to hypertension and progressive kidney damage. All tests were done on ALMS1 knockout rats, and the outcome was higher glomerular capillary pressure and increased arterial blood pressure. Blood flow dynamics were also affected by these changes.

Discovery

The Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK identified ''ALMS1'' as the single gene responsible for Alström syndrome.

References

Further reading

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External links

GeneReviews/NCBI/NIH/UW entry on Alstrom syndrome

OMIM entries on Alström syndrome

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