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Unser Haushund: Eine Spitzmaus im Wolfspelz? - Wolf-Ekkehard ...

Unser Haushund: Eine Spitzmaus im Wolfspelz? - Wolf-Ekkehard ... Unser Haushund: Eine Spitzmaus im Wolfspelz? - Wolf-Ekkehard ...

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70Fibroblast Growth Factor Receptor 3 (FGFR3) were identified shortly afterwards. FGFR3 mutationswere subsequently discovered for the TDs and hypochondroplasia (Figure 1).7-9 Remarkable degreesof genetic homogeneity and genotype:phenotype correlation soon became apparent as virtually allpatients with classic achondroplasia were found to have the same Gly380Arg mutation in thetransmembrane domain of this tyrosine kinase receptor. Similarly, all infants with TDII had theidentical Lys650Glu mutation in the distal kinase domain, whereas an Asn540Lys 113 mutation in theproximal kinase domain was detected in most patients with hypochondroplasia.7-9 Almost allinfants with TDI have mutations that introduce free cysteine residues in the proximal extracellularligand-binding domain of the receptor. Of note is that mutation of lysine 650 can produce 3 differentclinical phenotypes: conversion to glutamic acid results in TDII, conversion to methionine causesSADDAN, and conversion to serine leads to hypochondroplasia."Aus Horton (2006): http://www.gghjournal.com/volume22/4/featureArticle.cfm: "Figure 1. Domain structure of FGFR3 and major sites ofmutations. Ig: immunoglobulin, AB: acid box, TM: transmembrane, TKp/d: proximal and distal tyrosine kinase domains, ACH: achondroplasia,HYP: hypochondroplasia, TD: thanatophoric dysplasia, SADDAN: severe achondroplasia with developmental delay and acanthosis nigricans."Hortons folgende generelle Aussage zur Dominanz und Penetranz derAchondroplasie trifft auch auf die Hypochondroplasie zu 114 :"The penetrance of the achondroplasia mutation is 100%, meaning that individuals with FGFR3Gly380Arg mutation have achondroplasia [ebenso die Asn540Lys mutation in the proximal kinase domain bei derHypochondroplasie]. The vast majority of infants with FGFR3 mutations are born to parents withoutFGFR3 mutations, […..]”Zur Geschichte der Entdeckung und Revision einer Hypothese stellt derselbeAutor Folgendes fest:"After initial speculation that achondroplasia mutations cause loss-of-receptor function, it soon becameevident they actually result in gain of FGFR3 function, and the extent of this gain was found tocorrelate with the severity of the clinical phenotype. 17 The most compelling evidence came fromgenetic engineering experiments in mice in whom FGFR3 was either inactivated or the receptoractivated in cartilage by introducing achondroplasia or TD mutations, or by overexpressing ligands thatactivate FGFR3. 18-23 Mice in whom FGFR3 was inactivated had long bones, while mice with excessFGFR3 activation had short bones. Accordingly, FGFR3 mutations associated with achondroplasiaare often referred to as activating mutations."Und zur Funktion:"It is important to emphasize that FGFR3 is one of many physiologic regulators that modulate linearbone growth. Its normal function is as a negative regulator. The mutations associated withachondroplasia and related conditions are thought to act through exaggeration or enhancement ofthis normal physiologic function rather than through acquisition of new functions."113 "…lysine-for-asparagine substitution at codon 540 (N540K) in exon 10 and have been shown to cause hypochondroplasia [Bellus et al 1995, Prinos et al1995].” http://www.ncbi.nlm.nih.gov/books/NBK1477/ Francomano weist darauf hin, dass es vermutlich noch weitere Mutationen für dieHypochondroplasie gibt.114 Vgl. http://www.aruplab.com/files/technical-bulletins/Hypochondroplasia%20(FGFR3)%202%20Mutations.pdf undhttp://www.ncbi.nlm.nih.gov/books/NBK1477/

71Zuviel des Guten ist eben auch schlecht für den betroffenen Organismus. Esist also das gleiche Prinzip wie bei den Hunderassen mit Achondroplasie. Sieheauch die Ausführungen (Modell) zum Somatotropin oben.Clair A. Francomano (2005) zur Homozygotie-Frage beim Menschen:Hypochondroplasia-achondroplasia compound heterozygotes (FGFR3 N540K - G380R) have beenreported [McKusick et al 1973, Sommer et al 1987, Bellus et al 1995, Huggins et al 1999, Flynn &Pauli 2003]. The skeletal phenotype is more severe than typically found in achondroplasia, but unlikehomozygous achondroplasia, is compatible with survival. Ross et al [2003] described the phenotypein one child with compound heterozygosity for Leri-Weil dyschondrosteosis and hypochondroplasia.This child inherited both a SHOX deletion and the K540N FGFR3 mutation, and had severe shortstature with both rhizomelic and mesomelic shortening of the limbs.Soweit ich das bisher herausfinden konnte, wurde der Phänotyp derhomozygoten Hypochondroplasie jedoch noch nicht beschrieben, ("Thephenotype of homozygous hypochondroplasia has not yet been described;"(Francomano)). Zur homozygoten Achondroplasie hingegen vgl.http://www.lookfordiagnosis.com/cases.php?term=Achondroplasia&lang=1&filter=homozygous (2009).Falls die betroffenen Individuen mit homozygoter Hypochondroplasieebenfalls nicht lebensfähig sein sollten, bzw. deren Lebensfähigkeit starkeinschränkt wäre, würde das z. T. erklären, warum bisher solche (Direkt-)Mutanten im FGFR3-Gen nicht auch beim Haushund beschrieben worden sind.Sehen wir uns das FGFR3-Gen noch etwas näher an. Es kodiert beimMenschen für 806 (isoform 2: 808) Aminosäuren und "The displayed sequenceis further processed into a mature form” (http://www.uniprot.org/uniprot/P22607#section_seq)."This gene encodes a member of the fibroblast growth factor receptor (FGFR)family, with its amino acid sequence being highly conserved betweenmembers and among divergent species” (http://www.genecards.org/cgibin/carddisp.pl?gene=FGFR3;dort zahlreiche weitere Punkte). "Bisher wurden [beimMenschen] 28 Mutationen im FGFR3-Gen beschrieben, die mitKnochenmissbildungen, Blasenkarzinom, und Zervixkarzinom assoziiertwaren" (Schlüter/Seelig gemäß http://www.seelig.de/analysenspektrum/DOCS/00/FGFR3-Gen.html; zuden zahlreichen Defekten im Einzelnen vgl. die ausführliche Liste (wieder) unterhttp://www.genecards.org/cgi-bin/carddisp.pl?gene=FGFR3). Zur Funktion lesen im letzteren Dokument:"Function: Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors andplays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays anessential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and isrequired for normal skeleton development. Regulates both osteogenesis and postnatal bonemineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cellproliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL andFRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leadsto the production of the cellular signaling molecules diacylglycerol and inositol-1,4,5-trisphosphate.Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediatesactivation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well asof the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations thatlead to constitutive kinase activation or impair normal FGFR3 maturation, internalization anddegradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotesactivation of PTPN11/SHP2, STAT1, STAT5A and STAT5B."

71Zuviel des Guten ist eben auch schlecht für den betroffenen Organismus. Esist also das gleiche Prinzip wie bei den Hunderassen mit Achondroplasie. Sieheauch die Ausführungen (Modell) zum Somatotropin oben.Clair A. Francomano (2005) zur Homozygotie-Frage be<strong>im</strong> Menschen:Hypochondroplasia-achondroplasia compound heterozygotes (FGFR3 N540K - G380R) have beenreported [McKusick et al 1973, Sommer et al 1987, Bellus et al 1995, Huggins et al 1999, Flynn &Pauli 2003]. The skeletal phenotype is more severe than typically found in achondroplasia, but unlikehomozygous achondroplasia, is compatible with survival. Ross et al [2003] described the phenotypein one child with compound heterozygosity for Leri-Weil dyschondrosteosis and hypochondroplasia.This child inherited both a SHOX deletion and the K540N FGFR3 mutation, and had severe shortstature with both rhizomelic and mesomelic shortening of the l<strong>im</strong>bs.Soweit ich das bisher herausfinden konnte, wurde der Phänotyp derhomozygoten Hypochondroplasie jedoch noch nicht beschrieben, ("Thephenotype of homozygous hypochondroplasia has not yet been described;"(Francomano)). Zur homozygoten Achondroplasie hingegen vgl.http://www.lookfordiagnosis.com/cases.php?term=Achondroplasia&lang=1&filter=homozygous (2009).Falls die betroffenen Individuen mit homozygoter Hypochondroplasieebenfalls nicht lebensfähig sein sollten, bzw. deren Lebensfähigkeit starkeinschränkt wäre, würde das z. T. erklären, warum bisher solche (Direkt-)Mutanten <strong>im</strong> FGFR3-Gen nicht auch be<strong>im</strong> <strong>Haushund</strong> beschrieben worden sind.Sehen wir uns das FGFR3-Gen noch etwas näher an. Es kodiert be<strong>im</strong>Menschen für 806 (isoform 2: 808) Aminosäuren und "The displayed sequenceis further processed into a mature form” (http://www.uniprot.org/uniprot/P22607#section_seq)."This gene encodes a member of the fibroblast growth factor receptor (FGFR)family, with its amino acid sequence being highly conserved betweenmembers and among divergent species” (http://www.genecards.org/cgibin/carddisp.pl?gene=FGFR3;dort zahlreiche weitere Punkte). "Bisher wurden [be<strong>im</strong>Menschen] 28 Mutationen <strong>im</strong> FGFR3-Gen beschrieben, die mitKnochenmissbildungen, Blasenkarzinom, und Zervixkarzinom assoziiertwaren" (Schlüter/Seelig gemäß http://www.seelig.de/analysenspektrum/DOCS/00/FGFR3-Gen.html; zuden zahlreichen Defekten <strong>im</strong> Einzelnen vgl. die ausführliche Liste (wieder) unterhttp://www.genecards.org/cgi-bin/carddisp.pl?gene=FGFR3). Zur Funktion lesen <strong>im</strong> letzteren Dokument:"Function: Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors andplays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays anessential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and isrequired for normal skeleton development. Regulates both osteogenesis and postnatal bonemineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cellproliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL andFRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leadsto the production of the cellular signaling molecules diacylglycerol and inositol-1,4,5-trisphosphate.Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediatesactivation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well asof the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations thatlead to constitutive kinase activation or <strong>im</strong>pair normal FGFR3 maturation, internalization anddegradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotesactivation of PTPN11/SHP2, STAT1, STAT5A and STAT5B."

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