How ADAMTS2 Gene Cause EDS?

Mutation in the ADAMTS2 gene is responsible for 'Dermatosparaxis Types' of Ehlers-Danlos syndrome (EDS). These mutations greatly reduce the production/activity of the enzyme made by the ADAMTS2 gene. 

Procollagens cannot be processed correctly without this enzyme. As a result, collagen fibrils are not assembled properly — they appear ribbon-like and disorganized under the microscope. Cross-links, or chemical interactions, between collagen fibrils are also disrupted. These defects weaken connective tissue (the tissue that binds and supports the body's muscles, ligaments, organs, and skin), which leads to the signs and symptoms of the EDS.

Source: www.ghr.nlm.nih.gov

ADAMTS2 Gene … Normal Function

The ADAMTS2 gene provides instructions for making an enzyme that processes several types of ‘pro-collagen molecules’. We already discussed that ‘Procollagens’ are the precursors of collagens — which are complex molecules that add strength, support and elasticity (the ability to stretch) to many body tissues.

Specifically, the ADAMTS2 enzyme clips a short chain of protein building blocks (amino acids) of one end of procollagens. This clipping step is necessary for the collagen molecules to assemble into strong, slender fibrils outside cells.

Source: www.ghr.nlm.nih.gov

ADAMTS2 Gene … Location

Cytogenetic Location      :      5qter

Molecular Location         :      Chromosome 5

Base pairs (Bp) 178,537,851 - 178,772,430

The ADAMTS2 gene is located on the long (q) arm of ‘chromosome 5’ at the end (terminus) of the arm, more precisely, from BP 178,537,851 ~ 178,772,430 on chromosome 5.

Source: www.ghr.nlm.nih.gov

ADAMTS2 Gene ..... Official Name

ADAMTS2 gene is responsible for 'Dermatosparaxis Types' of Ehlers-Danlos syndrome (EDS)

Official Name        :      ADAM metallopeptidase with thrombospondin type 1 motif, 2

Official Symbol      :      ADAMTS2 

Other names of ADAMTS2 Gene

@ ADAM-TS2

@ A disintegrin and metalloproteinase with thrombospondin motifs 2

@ ATS2_HUMAN

@ hPCPNI

@ NPI

@ PCINP

@ PCPNI

@ pNPI

@ Procollagen I/II amino-propeptide processing enzyme

@ procollagen I N-proteinase

@ Procollagen N-endopeptidase

 Source: www.ghr.nlm.nih.gov

How COL1A2 Gene Cause EDS?

Several mutations in the COL1A2 gene are responsible for the ‘Arthrochalasia Type’ of Ehlers-Danlos Syndrome (EDS). These mutations, which affect one copy of the COL1A2 gene in each cell, delete a segment of the pro-α2 (I) chain that attaches one collagen molecule to another. The absence of this important segment prevents the normal assembly of type I collagen fibrils and alters the cross-linking between collagen molecules. These changes mainly affect tissues that are rich in type I collagen, such as the skin, bones, and tendons.

Rarely, mutations in both copies of the COL1A2 gene in each cell have been reported in people with the characteristic features of Ehlers-Danlos syndrome. These mutations prevent cells from producing any normal pro-α2 (I) chains. As a result, type I collagen fibrils in the skin and other tissues cannot be assembled correctly. The presence of abnormal collagen is associated with a variety of signs and symptoms, including loose joints, cardiac problems and other complications associated with Ehlers-Danlos syndrome.

Source: www.ghr.nlm.nih.gov

COL1A2 Gene … Normal Function

The COL1A2 gene provides instructions for making ‘type I collagen’. In my earlier post I already discussed about the Collagens — Collagens are a family of proteins that strengthen and support many tissues in the body, including cartilage, bone, tendon, skin, and the white part of the eye (the sclera). Type I collagen is the most abundant form of collagen in the human body.

The COL1A2 gene produces pro-α2 (I) chain in type I collagen.

I discussed in my COL1A1 post that ‘Collagens’ begin as procollagen molecules, which must be processed by enzymes outside the cell to remove extra protein segments from their ends. Each rope-like procollagen molecule is made up of 3 chains: 2 pro-α1(I) chains, produced from the COL1A1 gene, and 1 pro-α2(I) chain, produced from the COL1A2 gene.

After procollagens are processed, the resulting mature collagen molecules arrange themselves into long, thin fibrils. Individual collagen molecules are cross-linked to one another within these fibrils. The formation of cross-links results in very strong ‘type I’ collagen fibrils, which are found in the spaces around cells.

Source: www.ghr.nlm.nih.gov

COL1A2 Gene … Location

Cytogenetic Location      :      7q22.1

Molecular Location         :      Chromosome 7

Base pairs (Bp) 94,023,872 - 94,060,543

The COL1A2 gene is located on the long (q) arm of ‘chromosome 7’ at position 22.1, more precisely, from BP 94,023,872 ~ 94,060,543 on chromosome 7.

Source: www.ghr.nlm.nih.gov

COL1A2 ... Official Name

Like COL1A1, COL1A2 gene also responsible for 'Arthrochalasia Types' of Ehlers-Danlos syndrome (EDS)

Official Name

Official Name        :      collagen, type I, alpha 2

Official Symbol      :      COL1A2

Other names of COL5A2 Gene

@ alpha 2 collagen type I

@ CO1A2_HUMAN

@ Collagen I, alpha-2 polypeptide

@ Collagen of skin, tendon and bone, alpha-2 chain

Source: www.ghr.nlm.nih.gov

How COL1A1 Gene Cause EDS?

Several mutations in the COL1A1 gene are responsible for the ‘Arthrochalasia Type’ of Ehlers-Danlos Syndrome (EDS). These genetic changes lead to the production of defective pro-α1 (I) chain with missing a critical segment. The absence of this segment interferes with the assembly and structure of type I collagen molecules and the processing of these molecules into collagen fibrils.

Tissues that are rich in type I collagen — such as the skin, bones, and tendons are most affected by this change.

A mutation in the COL1A1 gene has also been shown to cause the ‘Classic Type’ of Ehlers-Danlos syndrome. This mutation changes one of the amino acids used to build the pro-α1 (I) chain. Specifically, this genetic change replaces the amino acid ‘arginine’ with the amino acid ‘cysteine’ at position 134. The altered protein interferes with other collagen-building proteins, disrupting the structure of type I collagen fibrils and trapping collagen in the cell. But researchers believe that this COL1A1 mutation only rarely underlies the signs and symptoms of classic Ehlers-Danlos syndrome.

Source: www.ghr.nlm.nih.gov 

COL1A1 Gene … Normal Function

The COL1A1 gene provides instructions for making ‘type I collagen’. In my earlier post I already discussed about the Collagens — Collagens are a family of proteins that strengthen and support many tissues in the body, including cartilage, bone, tendon, skin, and the white part of the eye (the sclera). Type I collagen is the most abundant form of collagen in the human body.

The COL1A1 gene produces pro-α1 (I) chain in type I collagen.

Collagens begin as procollagen molecules, which must be processed by enzymes outside the cell to remove extra protein segments from their ends. Each rope-like procollagen molecule is made up of 3 chains: 2 pro-α1(I) chains, produced from the COL1A1 gene, and 1 pro-α2(I) chain, produced from the COL1A2 gene. After procollagens are processed, the resulting mature collagen molecules arrange themselves into long, thin fibrils. Individual collagen molecules are cross-linked to one another within these fibrils. The formation of cross-links results in very strong type I collagen fibrils, which are found in the spaces around cells.

Source: www.ghr.nlm.nih.gov

COL1A1 Gene … Location

Cytogenetic Location      :      17q21.33

Molecular Location         :      Chromosome 17    

Base pairs (Bp) 48,261,456 - 48,278,999

The COL1A1 gene is located on the long (q) arm of ‘chromosome 17’ at position 21.33, more precisely, from BP 48,261,456 ~ 48,278,999 on chromosome 17.

Source: www.ghr.nlm.nih.gov

COL1A1 Gene ..... Official name

COL1A1 gene is responsible for 'Arthrochalasia Types' of Ehlers-Danlos syndrome (EDS)

Official Name        :      collagen, type I, alpha 1

Official Symbol      :      COL1A1

Other names of COL5A2 Gene

@ alpha 1 type I collagen preproprotein

@ CO1A1_HUMAN

@ COL1A1 protein

@ Collagen I, alpha-1 polypeptide

@ collagen of skin, tendon and bone, alpha-1 chain

@ type I collagen alpha 1

Source: www.ghr.nlm.nih.gov

How PLOD1 Gene Cause EDS?

More than 20 mutations have been identified in the PLOD1 gene which causes Kyphoscoliosis Types of EDS. The most common mutation duplicates a large portion of the gene, resulting in the production of a non-functional version of the ‘lysyl hydroxylase 1’ enzyme. Several other mutations introduce premature stop signals that prevent the gene from making any functional enzyme. A loss of lysyl hydroxylase 1 activity impairs cross-linking between collagen molecules. This disruption in the network of collagen fibrils weakens connective tissues, causing the signs and symptoms of Ehlers-Danlos syndrome.

Source: www.ghr.nlm.nih.gov

PLOD1 Gene … Normal Function

The PLOD1 gene provides instructions for making an enzyme called ‘lysyl hydroxylase 1’ — which modifies a particular amino acid called ‘lysine’, one of the building blocks used to make proteins. Specifically, ‘lysyl hydroxylase 1’ adds a single oxygen atom to a hydrogen atom to create a charged molecule called a ‘hydroxyl group’. Hydroxyl groups attach to some of the ‘lysines’ in collagen-like proteins. We already know that ‘Collagens’ are complex molecules which provide strength, support and elasticity (the ability to stretch) to many body tissues.

‘Hydroxyl groups’ are essential for collagen molecules to form stable interactions — called cross-links — with one another. Cross-links between these molecules allow collagen to form networks of strong, slender fibrils, which are an important part of the normal structure of connective tissue which binds and supports the body's muscles, ligaments, organs, and skin.

Source: www.ghr.nlm.nih.gov

PLOD1 Gene … Location

Cytogenetic Location      :      1p36.22

Molecular Location         :      Chromosome 1

Base pairs (Bp) 11,994,723 - 12,035,598

The PLOD1 gene is located on the long (q) arm of ‘chromosome 1’ at position 36.22, more precisely, from BP 11,994,723 ~ 12,035,598 on chromosome 1.

Source: www.ghr.nlm.nih.gov

PLOD1 Gene ... Official name

PLOD1 gene is responsible for 'Kyphoscoliosis Types'.

Official Name     :      procollagen-lysine,2-oxoglutarate 5-dioxygenase 1

Official Symbol      :      PLOD1

Other names of COL5A2 Gene

@ Collagen Lysyl Hydroxylase

@ LH

@ LH1

@ LLH

@ Lysine 2-Oxoglutarate Dioxygenase

@ Lysine Hydroxylase

@ Lysyl Hydroxylase

@ PLOD

@ PLOD1_HUMAN

@ Procollagen-L-lysine,2-oxoglutarate:oxygen oxidoreductase (5-hydroxylating)

@ procollagen-lysine 1, 2-oxoglutarate 5-dioxygenase 1

@ procollagen-lysine, 2-oxoglutarate 5-dioxygenase (lysine hydroxylase, Ehlers-Danlos syndrome type VI)

@ Protocollagen Lysyl Hydroxylase

Source: www.ghr.nlm.nih.gov

How COL3A1 Gene Cause EDS?

More than 320 mutations in the COL3A1 gene cause the ‘Vascular Type’ of Ehlers-Danlos Syndrome (EDS). Only a few of these mutations have been seen in more than one family. The mutations alter the structure and production of type III procollagen molecules. As a result, a large percentage of type III collagen molecules are assembled incorrectly or the amount of type III collagen is greatly reduced.

As per research, these changes affect tissues which are normally rich in this type of collagen such as the skin, blood vessels, and internal organs. Lack of sufficient type III collagen causes the signs and symptoms of ‘Vascular Ehlers-Danlos Syndrome’.

COL3A1 Gene … Normal Function

Type III collagen is found in tissues such as the skin, lungs, intestinal walls, and the walls of blood vessels. The COL3A1 gene produces the components of type III collagen, called pro-alpha1 (III) chains. 3 copies of this chain combine to make a molecule of type III procollagen. These triple-stranded, rope-like procollagen molecules must be processed by enzymes outside the cell to remove extra protein segments from their ends. Once these molecules are processed, the collagen molecules arrange themselves into long, thin fibrils. Within these fibrils, the individual collagen molecules are cross-linked to one another. These cross-links result in the formation of very strong mature type III collagen fibrils, which are found in the spaces around cells.

COL3A1 Gene … Location

Cytogenetic Location      :      2q31

Molecular Location         :      Chromosome 2

Base pairs (Bp) 189,839,098 - 189,877,471

The COL3A1 gene is located on the long (q) arm of ‘chromosome 2’ at position 31, more precisely, from BP 189,839,098 ~ 189,877,471 on chromosome 2.

Source: www.ghr.nlm.nih.gov

COL3A1 Gene ... Official Name

COL3A1 gene is responsible for 'Vascular Types', most severe form of Ehlers-Danlos syndrome (EDS)

Official Name        :      Collagen, type III, alpha 1

Official Symbol      :      COL3A1

Other names of COL5A2 Gene

@ alpha 1 type III collagen

@ CO3A1_HUMAN

@ collagen, fetal

@ Collagen III, alpha-1 polypeptide

@ Collagen, type III, alpha 1 (Ehlers-Danlos syndrome type IV, autosomal dominant)

@ EDS4A

Source: www.ghr.nlm.nih.gov