ResultsIndexgirlwithOI§  Novelone-nucleotideframeshiftduplicationc.141dupC(p.Tyr48Leufs*113)(Fig.2)Osteoporosisgroupandfracture-pronegroup§  5synonymoussinglenucleotidepolymorphisms(SNPs)

(Table1)

CRTAPvariantsinearly-onsetosteoporosisandrecurrentfractures

AliceCostantini,PhDstudentDepartmentofMolecularMedicineandSurgeryCMML8:02,KarolinskaUniversityHospital17176Stockholm,SwedenE-mail:alice.costantini@ki.se

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)