Could patients having this disease also have a Glycosylation problem?
Are they suffering from a form of Hereditary Multiple exostosis?
Do they have EXT gene Mutation?
By claiming the following:
"The mechanism of HME pathology is likely rooted in a disruption of the normal distribution of HS-binding growth factors, which include FGF and morphogens such as hedgehog, Wnt, and members of the TGF-β family. The loss of HS disrupts these pathways"
Hudson Freeze et al are reporting all the mechanisms involved in Basal cell breast cancer in one sentence and pin it down to Heparan surface. He is putting the disruption square and round in the Golgy Apparatus.
It makes perfect sense though, these diseases are triple negative pointing to an insensitive receptor
and sure enough we know that receptors are proteins, but in order to work, proteins need Glycosylation and Heparan Sulfate is :
"Heparan sulfate /hep·a·ran sul·fate/ (hep´ah-ran) is a glycosaminoglycan occurring in the cell membrane of most cells, consisting of a repeating disaccharide unit of glucosamine and uronic acid residues, which may be acetylated and sulfated; it accumulates in several mucopolysaccharidoses."(wikipedia)
Lack of Glycosylation will render receptor insensitive!
THIS IS THE FULL TEXT OF THEIR CLAIM:
Congenital Exostosis
Defects in the formation of heparan sulfate (HS) cause hereditary multiple
exostosis (HME), an autosomal dominant disease with a prevalence of about
1:50,000. It is caused by mutations in two genes EXT1 and
EXT2, which are involved in HS synthesis. HME patients have
bony outgrowths, usually at the growth plates of the long bones. Normally, the
growth plate contains chondrocytes in various stages of development, which are
enmeshed in an ordered matrix composed of collagen-chondroitin sulfate. In HME,
however, the outgrowths are often capped by disorganized cartilagenous masses
with chrondrocytes in different stages of development. About
1–2% of patients also develop osteosarcoma.
HME mutations occur in EXT1 (60–70%) and EXT2 (30–40%). The proteins encoded by these genes are thought to exist as a complex in the Golgi and both are required for polymerizing GlcNAcα1–4 and GlcAβ1–3 into HS. However, the partial loss of one allele of either gene appears sufficient to cause HME. This means that haploinsufficiency decreases the amount of HS and that EXT activity is rate limiting for HS biosynthesis. This is unusual because most glycan biosynthetic enzymes are in substantial excess.
The mechanism of HME pathology is likely rooted in a disruption of the normal distribution of HS-binding growth factors, which include FGF and morphogens such as hedgehog, Wnt, and members of the TGF-β family. The loss of HS disrupts these pathways in Drosophila. Mice that are null for either Ext gene are embryonic lethal and fail to gastrulate; however, Ext heterozygous animals are viable and about one third develop a visible exostoses on the ribs. No exostoses develop on the long bones of these animals (in contrast to patients with HME), but subtle chondrocyte growth abnormalities were seen in the growth plates of these bones. Further studies are needed to understand how truncation of the HS chains leads to ectopic growth plate formation and the phenotype abnormalities.
HME mutations occur in EXT1 (60–70%) and EXT2 (30–40%). The proteins encoded by these genes are thought to exist as a complex in the Golgi and both are required for polymerizing GlcNAcα1–4 and GlcAβ1–3 into HS. However, the partial loss of one allele of either gene appears sufficient to cause HME. This means that haploinsufficiency decreases the amount of HS and that EXT activity is rate limiting for HS biosynthesis. This is unusual because most glycan biosynthetic enzymes are in substantial excess.
The mechanism of HME pathology is likely rooted in a disruption of the normal distribution of HS-binding growth factors, which include FGF and morphogens such as hedgehog, Wnt, and members of the TGF-β family. The loss of HS disrupts these pathways in Drosophila. Mice that are null for either Ext gene are embryonic lethal and fail to gastrulate; however, Ext heterozygous animals are viable and about one third develop a visible exostoses on the ribs. No exostoses develop on the long bones of these animals (in contrast to patients with HME), but subtle chondrocyte growth abnormalities were seen in the growth plates of these bones. Further studies are needed to understand how truncation of the HS chains leads to ectopic growth plate formation and the phenotype abnormalities.
It becomes urgent to test EXT gene in these patients the TRAP1 gene
TRAP1,
Retinoblastoma protein.[5]
EXT1
From Wikipedia, the free encyclopedia
| Exostosin 1 | |||||
|---|---|---|---|---|---|
| Identifiers | |||||
| Symbols | EXT1; EXT; LGCR; LGS; TRPS2; TTV | ||||
| External IDs | OMIM: 608177 MGI: 894663 HomoloGene: 30957 GeneCards: EXT1 Gene | ||||
| EC number | 2.4.1.225 2.4.1.224, 2.4.1.225 | ||||
|
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| RNA expression pattern | |||||
 |
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 |
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| More reference expression data | |||||
| Orthologs | |||||
| Species | Human | Mouse | |||
| Entrez | 2131 | 14042 | |||
| Ensembl | ENSG00000182197 | ENSMUSG00000061731 | |||
| UniProt | Q16394 | P97464 | |||
| RefSeq (mRNA) | NM_000127 | NM_010162 | |||
| RefSeq (protein) | NP_000118 | NP_034292 | |||
| Location (UCSC) | Chr 8: 118.81 – 119.12 Mb |
Chr 15: 53.06 – 53.35 Mb |
|||
| PubMed search | [1] | [2] | |||
This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type I form of Multiple Exostoses.[1]
From Wikipedia, the free encyclopedia
| TNF receptor-associated protein 1 | |||||
|---|---|---|---|---|---|
| Identifiers | |||||
| Symbols | TRAP1; HSP 75; HSP75; HSP90L; TRAP-1 | ||||
| External IDs | OMIM: 606219 MGI: 1915265 HomoloGene: 9457 ChEMBL: 1075132 GeneCards: TRAP1 Gene | ||||
|
|||||
| RNA expression pattern | |||||
 |
|||||
| More reference expression data | |||||
| Orthologs | |||||
| Species | Human | Mouse | |||
| Entrez | 10131 | 68015 | |||
| Ensembl | ENSG00000126602 | ENSMUSG00000005981 | |||
| UniProt | Q12931 | Q9CQN1 | |||
| RefSeq (mRNA) | NM_001272049 | NM_026508 | |||
| RefSeq (protein) | NP_001258978 | NP_080784 | |||
| Location (UCSC) | Chr 16: 3.7 – 3.77 Mb |
Chr 16: 4.04 – 4.08 Mb |
|||
| PubMed search | [1] | [2] | |||
THESE 4 GENES NEEDS TO BE LOOKED AT ASAP IN TRIPLE NEGATIVE BREAST CANCER WITH BASALOID MORPHOLOGY!
