Dr. Urban and his research team are working to identify key molecules and processes of elastic fiber formation and maintenance. The insights from our research will hopefully be applied by others to understand common, complex diseases such as emphysema and aneurysms. So far, nine genes have been identified that cause cutis laxa or related diseases. Each gene is listed and briefly described below.

ELN	ATP6V0A2	SLC2A10
FBLN4 (EFEMP2)	PYCR1	LTBP4	RIN2
FBLN5	ALDH18A1	ATP7A	GORAB

The elastin (ELN) gene encodes (provides instructions for making) the protein of the same name. The elastin proteins bundle together to form part of the extracellular matrix, which exists between and around the body's cells to provide structural support for organs, including the lungs, blood vessels, skin, and other tissues. The extracellular matrix is abundant in connective tissues because it holds everything together. Some types of ELN mutations that completely destroy its protein product cause a condition caused supravalvular aortic stenosis. However, autosomal dominant cutis laxa (ADCL) is caused by mutations that cause the production of an abnormally long elastin protein, which is likely to interfere with its assembly into bundles and weakens the connective tissue in skin and blood vessels.

Dr. Urban's research on ELN: PubMed: 15955094;   PubMed: 16085695;   PubMed: 16374472;   PubMed: 20600892;   PubMed: 21309044;   PubMed: 22573328;   PubMed: 24758204;   PubMed: 26858344;   PubMed: 27866049;  

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The Fibulin 5 (FBLN5) gene's protein product is involved in the assembly of elastin protein into fibers. Mutations in FBLN5 can cause either autosomal dominant or autosomal recessive forms of cutis laxa. ADCL is caused by a mutation in one copy of the FBLN5 gene that results in half of the FBLN5 protein being abnormally long and not functioning properly. The abnormal half of this FBLN5 protein may interfere with the normal half, ultimately preventing proper bundling of the elastin fibers and resulting in weak connective tissue in the skin, organs, and blood vessels. Different FBLN5 mutations can cause autosomal recessive cutis laxa type 1A (ARCL1A). In ARCL1A, the mutations in both copies of this gene cause an altered structure of the protein product, preventing its transport out of the cells where it is produced and into the extracellular matrix. Without the FBLN5 protein product in the extracellular matrix, elastin is unable to bundle properly to create strong and flexible connective tissue.

Dr. Urban's research on FBLN5: PubMed: 17035250;   PubMed: 18267938;   PubMed: 19055655;   PubMed: 19167375;  

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The fibulin 4 (FBLN4 or EFEMP2) gene encodes for the fibulin 4 protein, also called "EGF containing fibulin-like extracellular matrix protein 2" or EFEMP2. The FBLN4 protein's function in the extracellular matrix is to bind and bring together different proteins that make the elastic fiber. Thus, it is involved in the assembly of elastic fibers and is found in all the same locations in the body where elastin is found. Mutations in FBLN4 cause autosomal recessive cutis laxa type 1B (ARCL1B).

Dr. Urban's research on FBLN4: PubMed: 16685658;   PubMed: 21563328;  

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The ATP6V0A2 gene codes for part of the V-ATPase protein complex, which helps control pH (acidity level) of cells and many cellular components as well as modification and transportation of other molecules within the cell. Mutations in this gene can cause autosomal recessive cutis laxa type 2A (ARCL2A) and have also been found in at least one patient with DeBarsy syndrome (ARCL3). Mutations in this gene affect the function of the V-ATPase, which is needed for the efficient secretion (production) of elastin by the cells. Mutations in ATP6V0A2 may also disrupt the modification of some other proteins, which in turn affect the formation of elastin bundles.

Dr. Urban's research on ATP6V0A2: PubMed: 19321599;   PubMed: 18157129;  

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Mutations in the PYCR1 gene cause autosomal recessive cutis laxa type 2B (ARCL2B). However, a mutation in this gene has also been found in at least one patient with DeBarsy syndrome syndrome type B (ARCL3B). The PYCR1 protein is an enzyme involved in the production of proline, an amino acid, which is an important building block of elastin. PYCR1 also protects against damage caused by the use of oxygen in chemical reactions inside the cells. Little is known about how mutations within this gene cause cutis laxa.

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Mutations in the ALDH18A1 (also called P5CS) gene cause autosomal recessive cutis laxa type 3 (ARCL3A), also known as DeBarsy syndrome type A. Similar to PYCR1, the ALDH18A1 protein is an enzyme involved in the production of proline, an amino acid, which is an important building block of elastin. ALDH18A1 also protects against damage caused by the use of oxygen in chemical reactions inside the cells.

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The ATP7A gene helps regulate copper levels in the body. Mutations in this gene prevent the body's cells from obtaining enough copper, which is necessary for the proper function of enzymes within many cell types, including bone, skin, and hair, as well as cells that comprise blood vessels and the nervous system. Mutations in the ATP7A gene that reduce the amount of ATP7A protein cause occipital horn syndrome (OHS), which is an X-linked recessive form of cutis laxa. Mutations in this gene that more extremely disrupt the amount and/or function of the ATP7A protein lead to the more severe Menkes syndrome.

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The SLC2A10 gene encodes the glucose transporter 10 (GLUT10) protein, which is involved in transporting glucose or vitamin C in the body. Mutations in this gene cause arterial tortuosity syndrome, which results in cardiovascular and connective tissue abnormalities, as well as hernias, particular facial features, and skin laxity. Arterial tortuosity syndrome can be difficult to distinguish from ARCL1B, caused by FLN4 mutations


Dr. Urban's research on SLC2A10: PubMed: 22116938

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The LTBP4 gene is thought to help form the structure of the extracellular matrix, as well as control the function of a growth factor, TGFβ, which in turn affects connective tissue and blood vessel walls. Mutations in the LTBP4 gene cause autosomal recessive cutis laxa type 1C (ARCL1C), also known as Urban-Rifkin-Davis syndrome, which is characterized by cutis laxa, as well as severe pulmonary, gastrointestinal, and urinary problems.

Dr. Urban's research on LTBP4: PubMed: 19836010;   PubMed: 22829427   PubMed: 25882708   PubMed: 26866239  

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The RAS and RAB interactor 2 (RIN2) gene causes the autosomal recessive disorder MACS syndrome. MACS is an acronym for macrocephaly (large head), alopecia (sparse hair), cutis laxa, and scoliosis. The RIN2 protein helps transport and sort other proteins necessary for the formation of elastic fibers.

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The GORAB gene codes for a RAB6-interacting golgin, also called SCYL1BP1. The GORAB protein function is not completely understood, but one function may be the modification and transportation of other proteins within the cell. Mutations in GORAB may therefore disrupt the modification and transportation of these other proteins, which in turn affect the formation of elastin bundles. Mutations in the GORAB (SCYL1BP1) gene cause geroderma osteodysplasticum (GO), which is an autosomal recessive form of cutis laxa that occurs in babies or young children. These children have loose skin, mostly on the hands, feet, and stomach, as well as their face. Other features include a small jaw, hip dislocations, hernias, osteoporosis, fractures, and sometimes dwarfism. There are typically neither cardiovascular nor pulmonary symptoms.

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