ResultsIndexgirlwithOI§ Novelone-nucleotideframeshiftduplicationc.141dupC(p.Tyr48Leufs*113)(Fig.2)Osteoporosisgroupandfracture-pronegroup§ 5synonymoussinglenucleotidepolymorphisms(SNPs)
(Table1)
CRTAPvariantsinearly-onsetosteoporosisandrecurrentfractures
AliceCostantini,PhDstudentDepartmentofMolecularMedicineandSurgeryCMML8:02,KarolinskaUniversityHospital17176Stockholm,SwedenE-mail:[email protected]
AliceCostantini1,IlkkaVuorimies2,3,RiikkaMäkitie2,MerviKMäyränpää3,JuttaBecker4,MinnaPekkinen2,3,HelenaValta3,ChristianNetzer4,AndersKämpe1,FulyaTaylan1,HongJiao5,6andOutiMäkitie1,2,3,7
1DepartmentofMolecularMedicineandSurgeryandCenterforMolecularMedicine,KarolinskaInstitutet,Stockholm,Sweden,2FolkhälsanInstituteofGeneticsandUniversityofHelsinki,Helsinki,Finland,3Children'sHospital,UniversityofHelsinkiandHelsinkiUniversityHospital,Helsinki,Finland,4InstituteofHumanGenetics,UniversityofCologne,Cologne,Germany,5DepartmentofBiosciencesandNutrition,ScienceforLifeLaboratory,KarolinskaInstitutet,Stockholm,Sweden,6ClinicalResearchCentre,KarolinskaUniversityHospital,Huddinge,Sweden,7DepartmentofClinicalGenetics,KarolinskaUniversity
Hospital,Stockholm,Sweden
Patients1) Eleven-year-old Iraqi girl with severe osteogenesis
imperfecta(OI)(Fig.1)2)Osteoporosisgroup(30patients).Inclusioncriteria:
§ aBMDZ-scorebelow-2.0and/or§ a history of increased bone fragility (at least three
peripheral fractures and/or one or more vertebralcompressionfractures)
§ exclusionofsecondaryosteoporosisand§ age below 30 years before the diagnosis of
osteoporosis3)Fracture-pronegroup(66patients).Inclusioncriteria:
§ agebetween4-16years§ a history of at least two low-energy long bone
fracturesbeforeage10years,threelow-energylongbone fractures before age 16 years, and/or at leastonelow-energyvertebralcompressionfracture
Methods§ Homozygositymappingwith1-2STS-markers§ Sangersequencing
IntroductionEarly-onsetosteoporosispresentsasboneweaknessandincreased risk of fractures in children and young adults.Thegeneticcausesandmolecularmechanismsunderlyingthis disease are poorly defined. However, the study ofother rare bone diseases has recently led to theidentificationofnewgenescausingosteoporosis.
AimoftheprojectTo explore the role of variations in the cartilage-associated protein (CRTAP) gene in early-onsetosteoporosisand/orrecurrentfractures.
Conclusions
Table 1 Genetic variants identified in the CRTAP gene. The minor allelefrequencies(MAFs)werecomparabletohealthypopulation(p>0.05)
Fig. 2 Pedigree of the family and Sangerelectropherograms of the frameshiftmutation c.141dupC (p.Tyr48Leufs*113).Themutation is homozygous in the indexgirl whereas her consanguineous parentsarehealthycarriers.The indexpatienthastwo healthy sisters and two healthybrothers.Thethirdbrotherdiedearlyafterbirth because of a similar skeletalphenotype. Abbreviations: wt=wild type,mut=mutated; Ala=Alanine; Tyr=Tyrosine;Arg=Arginine;Leu=Leucine;Pro=Proline
Fig. 3Aschematic representationof theCRTAPgene and location of all exonic and intronicpathogenic variants that have previously beenreportedinliterature,markedonleftsideofthediagram. All the genetic variants found in ourstudy,thec.141dupCandthe5SNPs,aremarkedontherightsideofthefigure
§ We identified a novel CRTAPhomozygousmutation,
§ c.141dupC, in a girl with severeOI(Fig.3)
§ Weconfirmedabsenceofcarrierphenotypeinherparents
§ We exc luded monoal le l i cvariants in CRTAP as commonrisk factors for milder skeletalfragility
Authorsdeclarethereisnoconflictofinterest
P484
F i g . 1 I n d e x p a t i e n t ’ sradiographs at 11 years beforebisphosphonate treatment.She has small, narrow thorax(A) and severe kyphoscoliosis(B) with spinal compressionfractures involving the wholespine (B). All long bones inarms (C) and legs (D-F) ares h o r t , d e f o rmed a n dosteoporotic. Metaphysealregions are wide and show"pop-corn" - l i ke i r regu larcalcification(C-F)
