nach oben

Child's Nervous System

Erschienen in:

01.09.2012 | Special Annual Issue

Phenotype profile of a genetic mouse model for Muenke syndrome

verfasst von: Hyun-Duck Nah, Eiki Koyama, Nneamaka B. Agochukwu, Scott P. Bartlett, Maximilian Muenke

Erschienen in: Child's Nervous System | Ausgabe 9/2012

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The Muenke syndrome mutation (FGFR3 ^P250R), which was discovered 15 years ago, represents the single most common craniosynostosis mutation. Muenke syndrome is characterized by coronal suture synostosis, midface hypoplasia, subtle limb anomalies, and hearing loss. However, the spectrum of clinical presentation continues to expand. To better understand the pathophysiology of the Muenke syndrome, we present collective findings from several recent studies that have characterized a genetically equivalent mouse model for Muenke syndrome (FgfR3 ^P244R) and compare them with human phenotypes.

Conclusions

FgfR3 ^P244R mutant mice show premature fusion of facial sutures, premaxillary and/or zygomatic sutures, but rarely the coronal suture. The mice also lack the typical limb phenotype. On the other hand, the mutant mice display maxillary retrusion in association with a shortening of the anterior cranial base and a premature closure of intersphenoidal and spheno-occipital synchondroses, resembling human midface hypoplasia. In addition, sensorineural hearing loss is detected in all FgfR3 ^P244R mutant mice as in the majority of Muenke syndrome patients. It is caused by a defect in the mechanism of cell fate determination in the organ of Corti. The mice also express phenotypes that have not been previously described in humans, such as reduced cortical bone thickness, hypoplastic trabecular bone, and defective temporomandibular joint structure. Therefore, the FgfR3 ^P244R mouse provides an excellent opportunity to study disease mechanisms of some classical phenotypes of Muenke syndrome and to test novel therapeutic strategies. The mouse model can also be further explored to discover previously unreported yet potentially significant phenotypes of Muenke syndrome.

Agochukwu NB, Solomon BD, Doherty ES, Muenke M (2012) The palatal and oral manifestations of Muenke syndrome (FGFR3-related craniosynostosis). J Craniofac Surg (in press)

Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, Kaitila I, McIntosh I, Francomano CA (1995) Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 56:368–373PubMed

Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10:357–359PubMedCrossRef

Bellus GA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, Francomano CA, Muenke M (1996) Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet 14:174–176PubMedCrossRef

Boulet SL, Rasmussen SA, Honein MA (2008) A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet A 146A:984–991PubMedCrossRef

Chellaiah AT, McEwen DG, Werner S, Xu J, Ornitz DM (1994) Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain III creates a receptor highly specific for acidic FGF/FGF-1. J Biol Chem 269:11620–11627PubMed

Chen L, Li C, Qiao W, Xu X, Deng C (2001) A Ser(365)– > Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 10:457–465PubMedCrossRef

Collman H, Schweitzer T, Bohm H (2011) Imaging studies and neurosurgical treatment. In: Muenke M KW, Collman H, Solomon BD (ed) Monographs in Human Genetics Craniosynostoses: Molecular Genetics, Principles of Diagnosis and Treatment. Karger Publishing, Basel, pp 216–231

Colvin JS, Bohne BA, Harding GW, McEwen DG, Ornitz DM (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet 12:390–397PubMedCrossRef

10.

de Jong T, Mathijssen IM, Hoogeboom AJ (2011) Additional phenotypic features of Muenke syndrome in 2 Dutch families. J Craniofac Surg 22:571–575PubMedCrossRef

11.

de Jong T, Toll MS, de Gier HH, Mathijssen IM (2011) Audiological profile of children and young adults with syndromic and complex craniosynostosis. Arch Otolaryngol Head Neck Surg 137:775–778PubMedCrossRef

12.

Deng C, Wynshaw-Boris A, Zhou F, Kuo A, Leder P (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84:911–921PubMedCrossRef

13.

Doherty ES, Lacbawan F, Hadley DW, Brewer C, Zalewski C, Kim HJ, Solomon B, Rosenbaum K, Domingo DL, Hart TC, Brooks BP, Immken L, Lowry RB, Kimonis V, Shanske AL, Jehee FS, Bueno MR, Knightly C, McDonald-McGinn D, Zackai EH, Muenke M (2007) Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature. Am J Med Genet A 143A:3204–3215PubMedCrossRef

14.

Escobar LF, Hiett AK, Marnocha A (2009) Significant phenotypic variability of Muenke syndrome in identical twins. Am J Med Genet A 149A:1273–1276PubMedCrossRef

15.

Fakhry A, Ratisoontorn C, Vedhachalam C, Salhab I, Koyama E, Leboy P, Pacifici M, Kirschner RE, Nah HD (2005) Effects of FGF-2/-9 in calvarial bone cell cultures: differentiation stage-dependent mitogenic effect, inverse regulation of BMP-2 and noggin, and enhancement of osteogenic potential. Bone 36:254–266PubMedCrossRef

16.

Glass IA, Chapman S, Hockley AD (1994) A distinct autosomal dominant craniosynostosis-brachydactyly syndrome. Clin Dysmorphol 3:215–223PubMed

17.

Graham JM Jr, Braddock SR, Mortier GR, Lachman R, Van Dop C, Jabs EW (1998) Syndrome of coronal craniosynostosis with brachydactyly and carpal/tarsal coalition due to Pro250Arg mutation in FGFR3 gene. Am J Med Genet 77:322–329PubMedCrossRef

18.

Harada M, Murakami H, Okawa A, Okimoto N, Hiraoka S, Nakahara T, Akasaka R, Shiraishi Y, Futatsugi N, Mizutani-Koseki Y, Kuroiwa A, Shirouzu M, Yokoyama S, Taiji M, Iseki S, Ornitz DM, Koseki H (2009) FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nat Genet 41:289–298PubMedCrossRef

19.

Honnebier MB, Cabiling DS, Hetlinger M, McDonald-McGinn DM, Zackai EH, Bartlett SP (2008) The natural history of patients treated for FGFR3-associated (Muenke-type) craniosynostosis. Plast Reconstr Surg 121:919–931PubMedCrossRef

20.

Ibrahimi OA, Zhang F, Eliseenkova AV, Linhardt RJ, Mohammadi M (2004) Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. Hum Mol Genet 13:69–78PubMedCrossRef

21.

Jacques BE, Montcouquiol ME, Layman EM, Lewandoski M, Kelley MW (2007) Fgf8 induces pillar cell fate and regulates cellular patterning in the mammalian cochlea. Development 134:3021–3029PubMedCrossRef

22.

Keller MK, Hermann NV, Darvann TA, Larsen P, Hove HD, Christensen L, Schwartz M, Marsh JL, Kreiborg S (2007) Craniofacial morphology in Muenke syndrome. J Craniofac Surg 18:374–386PubMedCrossRef

23.

Krejci P, Prochazkova J, Bryja V, Jelinkova P, Pejchalova K, Kozubik A, Thompson LM, Wilcox WR (2009) Fibroblast growth factor inhibits interferon gamma-STAT1 and interleukin 6-STAT3 signaling in chondrocytes. Cell Signal 21:151–160PubMedCrossRef

24.

Lajeunie E, El Ghouzzi V, Le Merrer M, Munnich A, Bonaventure J, Renier D (1999) Sex related expressivity of the phenotype in coronal craniosynostosis caused by the recurrent P250R FGFR3 mutation. J Med Genet 36:9–13PubMed

25.

Laurita J, Koyama E, Chin B, Taylor JA, Lakin GE, Hankenson KD, Bartlett SP, Nah HD (2011) The Muenke syndrome mutation (FgfR3P244R) causes cranial base shortening associated with growth plate dysfunction and premature perichondrial ossification in murine basicranial synchondroses. Dev Dyn 240:2584–2596PubMedCrossRef

26.

Madeline LA, Elster AD (1995) Suture closure in the human chondrocranium: CT assessment. Radiology 196:747–756PubMed

27.

Mansour SL, Twigg SR, Freeland RM, Wall SA, Li C, Wilkie AO (2009) Hearing loss in a mouse model of Muenke syndrome. Hum Mol Genet 18:43–50PubMedCrossRef

28.

Matsunobu T, Torigoe K, Ishikawa M, de Vega S, Kulkarni AB, Iwamoto Y, Yamada Y (2009) Critical roles of the TGF-beta type I receptor ALK5 in perichondrial formation and function, cartilage integrity, and osteoblast differentiation during growth plate development. Dev Biol 332:325–338PubMedCrossRef

29.

Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bukulmez H, Balmes G, Krejci P, Mekikian PB, Otani K, Yamaura I, Warman ML, Givol D, Murakami S (2009) FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Hum Mol Genet 18:227–240PubMedCrossRef

30.

McBratney-Owen B, Iseki S, Bamforth SD, Olsen BR, Morriss-Kay GM (2008) Development and tissue origins of the mammalian cranial base. Dev Biol 322:121–132PubMedCrossRef

31.

Minina E, Kreschel C, Naski MC, Ornitz DM, Vortkamp A (2002) Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev Cell 3:439–449PubMedCrossRef

32.

Moloney DM, Wall SA, Ashworth GJ, Oldridge M, Glass IA, Francomano CA, Muenke M, Wilkie AO (1997) Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis. Lancet 349:1059–1062PubMedCrossRef

33.

Morriss-Kay GM, Wilkie AO (2005) Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J Anat 207:637–653PubMedCrossRef

34.

Mueller KL, Jacques BE, Kelley MW (2002) Fibroblast growth factor signaling regulates pillar cell development in the organ of corti. J Neurosci 22:9368–9377PubMed

35.

Muenke M, Schell U (1995) Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet 11:308–313PubMedCrossRef

36.

Muenke M, Gripp KW, McDonald-McGinn DM, Gaudenz K, Whitaker LA, Bartlett SP, Markowitz RI, Robin NH, Nwokoro N, Mulvihill JJ, Losken HW, Mulliken JB, Guttmacher AE, Wilroy RS, Clarke LA, Hollway G, Ades LC, Haan EA, Mulley JC, Cohen MM Jr, Bellus GA, Francomano CA, Moloney DM, Wall SA, Wilkie AO et al (1997) A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am J Hum Genet 60:555–564PubMed

37.

Murakami S, Kan M, McKeehan WL, de Crombrugghe B (2000) Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A 97:1113–1118PubMedCrossRef

38.

Naski MC, Wang Q, Xu J, Ornitz DM (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet 13:233–237PubMedCrossRef

39.

Naski MC, Colvin JS, Coffin JD, Ornitz DM (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125:4977–4988PubMed

40.

Okamoto K, Ito J, Tokiguchi S, Furusawa T (1996) High-resolution CT findings in the development of the sphenooccipital synchondrosis. AJNR Am J Neuroradiol 17:117–120PubMed

41.

Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (1996) Receptor specificity of the fibroblast growth factor family. J Biol Chem 271:15292–15297PubMedCrossRef

42.

Pickles JO (2001) The expression of fibroblast growth factors and their receptors in the embryonic and neonatal mouse inner ear. Hear Res 155:54–62PubMedCrossRef

43.

Reardon W, Wilkes D, Rutland P, Pulleyn LJ, Malcolm S, Dean JC, Evans RD, Jones BM, Hayward R, Hall CM, Nevin NC, Baraister M, Winter RM (1997) Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis. J Med Genet 34:632–636PubMedCrossRef

44.

Rice DP, Rice R, Thesleff I (2003) Fgfr mRNA isoforms in craniofacial bone development. Bone 33:14–27PubMedCrossRef

45.

Ridgway EB, Wu JK, Sullivan SR, Vasudavan S, Padwa BL, Rogers GF, Mulliken JB (2011) Craniofacial growth in patients with FGFR3Pro250Arg mutation after fronto-orbital advancement in infancy. J Craniofac Surg 22:455–461PubMedCrossRef

46.

Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371:252–254PubMedCrossRef

47.

Sabatino G, Di Rocco F, Zampino G, Tamburrini G, Caldarelli M, Di Rocco C (2004) Muenke syndrome. Childs Nerv Syst 20:297–301PubMedCrossRef

48.

Shim K, Minowada G, Coling DE, Martin GR (2005) Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. Dev Cell 8:553–564PubMedCrossRef

49.

Thomas GP, Wilkie AO, Richards PG, Wall SA (2005) FGFR3 P250R mutation increases the risk of reoperation in apparent ‘nonsyndromic’ coronal craniosynostosis. J Craniofac Surg 16:347–352, discussion 353–344PubMedCrossRef

50.

Twigg SR, Healy C, Babbs C, Sharpe JA, Wood WG, Sharpe PT, Morriss-Kay GM, Wilkie AO (2009) Skeletal analysis of the Fgfr3(P244R) mouse, a genetic model for the Muenke craniosynostosis syndrome. Dev Dyn 238:331–342PubMedCrossRef

51.

Wilkie AO, Oldridge M, Tang Z, Maxson RE Jr (2001) Craniosynostosis and related limb anomalies. Novartis Found Symp 232:122–133, discussion 133–143PubMedCrossRef

52.

Wilkie AO, Byren JC, Hurst JA, Jayamohan J, Johnson D, Knight SJ, Lester T, Richards PG, Twigg SR, Wall SA (2010) Prevalence and complications of single-gene and chromosomal disorders in craniosynostosis. Pediatrics 126:e391–e400PubMedCrossRef

53.

Wu XL, Gu MM, Huang L, Liu XS, Zhang HX, Ding XY, Xu JQ, Cui B, Wang L, Lu SY, Chen XY, Zhang HG, Huang W, Yuan WT, Yang JM, Gu Q, Fei J, Chen Z, Yuan ZM, Wang ZG (2009) Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. Am J Hum Genet 85:53–63PubMedCrossRef

54.

Yasuda T, Nah HD, Laurita J, Kinumatsu T, Shibukawa Y, Shibutani T, Minugh-Purvis N, Pacific M, Koyama E (2012) Muenke syndrome mutation, FgfR3(P244R), causes TMJ defects in postnatal mice. J Dent Res (in press)

55.

Zhang R, Murakami S, Coustry F, Wang Y, de Crombrugghe B (2006) Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. Proc Natl Acad Sci U S A 103:365–370PubMedCrossRef

56.

Zhou G, Schwartz LT, Gopen Q (2009) Inner ear anomalies and conductive hearing loss in children with Apert syndrome: an overlooked otologic aspect. Otol Neurotol 30:184–189PubMedCrossRef

Titel: Phenotype profile of a genetic mouse model for Muenke syndrome
verfasst von: Hyun-Duck Nah
Eiki Koyama
Nneamaka B. Agochukwu
Scott P. Bartlett
Maximilian Muenke
Publikationsdatum: 01.09.2012
Verlag: Springer-Verlag
Erschienen in: Child's Nervous System / Ausgabe 9/2012
Print ISSN: 0256-7040
Elektronische ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-012-1778-9

Neu im Fachgebiet Chirurgie

Vorsicht, erhöhte Blutungsgefahr nach PCI!

10.05.2024 Koronare Herzerkrankung Nachrichten

Nach PCI besteht ein erhöhtes Blutungsrisiko, wenn die Behandelten eine verminderte linksventrikuläre Ejektionsfraktion aufweisen. Das Risiko ist umso höher, je stärker die Pumpfunktion eingeschränkt ist.

Darf man die Behandlung eines Neonazis ablehnen?

08.05.2024 Gesellschaft Nachrichten

In einer Leseranfrage in der Zeitschrift Journal of the American Academy of Dermatology möchte ein anonymer Dermatologe bzw. eine anonyme Dermatologin wissen, ob er oder sie einen Patienten behandeln muss, der eine rassistische Tätowierung trägt.

Deutlich weniger Infektionen: Wundprotektoren schützen!

08.05.2024 Postoperative Wundinfektion Nachrichten

Der Einsatz von Wundprotektoren bei offenen Eingriffen am unteren Gastrointestinaltrakt schützt vor Infektionen im Op.-Gebiet – und dient darüber hinaus der besseren Sicht. Das bestätigt mit großer Robustheit eine randomisierte Studie im Fachblatt JAMA Surgery.

Chirurginnen und Chirurgen sind stark suizidgefährdet

07.05.2024 Suizid Nachrichten

Der belastende Arbeitsalltag wirkt sich negativ auf die psychische Gesundheit der Angehörigen ärztlicher Berufsgruppen aus. Chirurginnen und Chirurgen bilden da keine Ausnahme, im Gegenteil.

Update Chirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Aktuelle BDC Leitlinien-Webinare

S3-Leitlinie „Diagnostik und Therapie des Karpaltunnelsyndroms“

Karpaltunnelsyndrom BDC Leitlinien Webinare

CME: 2 Punkte

Das Karpaltunnelsyndrom ist die häufigste Kompressionsneuropathie peripherer Nerven. Obwohl die Anamnese mit dem nächtlichen Einschlafen der Hand (Brachialgia parästhetica nocturna) sehr typisch ist, ist eine klinisch-neurologische Untersuchung und Elektroneurografie in manchen Fällen auch eine Neurosonografie erforderlich. Im Anfangsstadium sind konservative Maßnahmen (Handgelenksschiene, Ergotherapie) empfehlenswert. Bei nicht Ansprechen der konservativen Therapie oder Auftreten von neurologischen Ausfällen ist eine Dekompression des N. medianus am Karpaltunnel indiziert.

Prof. Dr. med. Gregor Antoniadis

S2e-Leitlinie „Distale Radiusfraktur“

Radiusfraktur BDC Leitlinien Webinare

CME: 2 Punkte

Das Webinar beschäftigt sich mit Fragen und Antworten zu Diagnostik und Klassifikation sowie Möglichkeiten des Ausschlusses von Zusatzverletzungen. Die Referenten erläutern, welche Frakturen konservativ behandelt werden können und wie. Das Webinar beantwortet die Frage nach aktuellen operativen Therapiekonzepten: Welcher Zugang, welches Osteosynthesematerial? Auf was muss bei der Nachbehandlung der distalen Radiusfraktur geachtet werden?

PD Dr. med. Oliver Pieske

Dr. med. Benjamin Meyknecht

S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“

Appendizitis BDC Leitlinien Webinare

CME: 2 Punkte

Inhalte des Webinars zur S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“ sind die Darstellung des Projektes und des Erstellungswegs zur S1-Leitlinie, die Erläuterung der klinischen Relevanz der Klassifikation EAES 2015, die wissenschaftliche Begründung der wichtigsten Empfehlungen und die Darstellung stadiengerechter Therapieoptionen.

Dr. med. Mihailo Andric

Springer Medizin

Abstract

Purpose

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 9/2012

Atypical scaphocephaly: a review

Introduction for presidential address by Dr Paul Steinbok, President of the ISPN, 2011, Goa India, October 2011

Anterior plagiocephaly: epidemiology, clinical findings,diagnosis, and classification. A review

Posterior plagiocephaly

Spring-assisted correction of sagittal suture synostosis

40th Annual Meeting of the International Society for Pediatric Neurosurgery, Sydney, Australia, September 9-13, 2012

Update Chirurgie