Inactivating mutation in the acid-labile subunit gene: a new cause of growth retardation, pubertal delay and insulin resitance?

DOMENÉ HM; BENGOLEA SV; MARTINEZ A; ROPELATO MG; PENNISI P; SCAGLIA P; HEINRICH JJ

Baltimore, MD

Congreso; Lawson Wilkins Pediatric Endocrine Society Annual Meeting,; 2002

LWEP

1nsulin-likegrowthfactor1(1GF-1)circulatespredominantlyasaternarycomplexof150kDaboundto1GFbindingprotein-3or-5(1GFBP-3,-5)andanacid-labilesubunit(ALS).ALSstabilizesthe1GF-II1GFBPcomplexes,reducesthepassageofthe1GFstatheextravascularcompartment,andextendstheirhalf-life.Wede-scribea17-year-oldboywithdelayofgrowthandpubelialdevel-opment.Dataregardinggestationandperinatalperiodswerenotavailablebecausetheboywasadoptedatoneweekofage.At16.4yrheightwas154.1cm(-2.17SD),weight41.8kg(-2.0SD),BM117.9kgjm2,TannerstageIII,testesS/lOml.psychoma-torandneurologicaldevelopmentwerenormal.Laboratoryanaly-sisruledouthematological,liver,andrenaldiseases.Growthhormone(GH)responsetoprovocativetestwasnormal(31.0nglmI)butspontaneoussecretionwasincreased(18.9±12.6nglmI).Both1GF-1(31ng/ml;-5.28SD)and1GFBP-3(0.22~Lg/ml;-9.7SD)wereextremelylow.BasalALSwasundetectable«0.2~Lg/ml).An1GF-1generationtestanda6-monthGHtreatmentperiodwereineffectivetoinduceanychangesin1GF-I,1GFBP-3,arALScirculatinglevels,aswellastoimprovegrowthvelocity.Unde-tectablebasalandstimulatedALSleveIsorientedtheinvestigatiantothestudyoftheIGFALSgene.Sequencingofthecompletecad-ingregionofthisgenerevealedahomozygousdeletionofagua-nine,resultinginthesubstitutionofLysforGluatcadon35,andtheappearanceofastopcodonatpasition120ofpre-ALS(E35i1,120x),predictingtheformationofatruncated,mostlikelyinac-tiveprotein.ThismutationdoesnotseemtobefrequentintheAr-gentineanpopulationsinceitwasnotfoundin60healthyc011trols.Agennlinechromosomalnondisjunctio11eventisun-likelybecausethepatientresultedheterozygousfortwohighlyvariablemicrosatellites(D16S521andD16S3024)locatedinthe16p13.3region,neartothe1GFALSlocus.CirculatingALSproteinwasundetectablebywesternimmunoblotingusingN-orC-termi-nusanti-ALSantibodies.Serumfromthepatientwasunabletoformtheternarycomplexexaminedbycross-linkingandsizeexclusioncolumnchrornatography,evenafterGHtreatment.