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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/