Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3 |
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Authors: | Cruts Marc; Backhovens Hubert; Wang Sheng-Yue; Van Gassen Geert; Theuns Jessie; De Jonghe Chris; Wehnert Anita; De Voecht Joke; De Winter Goedele; Cras Patrick; Bruyland Marc; Datson Nicole; Weissenbach Jean; Dunnen Johan Tden; Martin Jean-Jaques; Hendriks Lydia; Van Broeckhoven Christine |
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Institution: | Laboratory of Neurogenetics, Flemish Institute for Biotechnology, Born-Bunge Foundation, University of Antwerp (UIA), Department of Biochemistry, Universiteitsplein 1 B-2610 Antwerpen
1Laboratories of Neuropathology and Neuroiology, Born-Bunge Foundation, University of Antwarp (UIA). Department of Medicine B-2610 Antwerpen
2Department of Neurology, City Hospital of Ronse, B-9600 Ronse and Department of Neurology, University of Brussels (VUB) B-1090 Brussels, Belgium
3Department of Human Genetics, Leiden University, Medical Genetics Center Zuid-West Nederland 2333 AL Leiden, the Netherlands
4Généthon, 1 rue de I'Internationale BP60 F-91002 Evry, France |
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Abstract: | Genetic linkage studies have indicated that chromosome 14q24.3harbours a major locus for early-onset (onset age <65 years)Alzheimer's disease (AD3). Positional cloning efforts have identifieda novel gene S182 or presenilin 1 as the AD3 gene. We have mappedS182 in the AD3 candidate region between D14S277 and D14S284defined by genetic linkage studies in the two chromosome 14linked, early-onset AD families AD/A and AD/B. We have shownthat S182 is expressed in lymphoblasts and have determined thecomplete cDNA in both brain and lymphoblasts by RT-PCR sequencing.S182 is alternatively spliced in both brain and lymphoblastswithin a putative phosphorylation site located 5' in the codingregion. We identified two novel mutations, Ile143Thr and Gly384Alalocated in, respectively, the second transmembrane domain andin the sixth hydrophilic loop of the putative transmembranestructure of S182. As families AD/A and AD/B have a very similarAD phenotype our observation of two mutations in functionallydifferent domains suggest that onset age and severity of ADmay not be very helpful predictors of the location of putativeS182 mutations. |
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