title: The breakpoint identified in a balanced de novo translocation t(7;9)(p14.1;q31.3) disrupts the A-kinase (PRKA) anchor protein 2 gene (AKAP2) on chromosome 9 in a patient with Kallmann syndrome and bone anomalies.
abstract: We report the molecular characterization of a patient with Kallmann syndrome and bone anomalies bearing a balanced de novo translocation t(7;9)(p14.1;q31.3) which completely disrupts the A-kinase anchor protein 2 gene (AKAP2) on chromosome 9. In order to investigate the role of AKAP2 in the pathogenesis of the disease, we analyzed the expression of Akap2 in mouse embryos. The expression pattern was consistent with the phenotype observed and mAkap2 was actually found in the olfactory bulb and in the cartilagineous structures of the embryo. Since AKAP2 is supposed to bind and compartmentalize the PKA, we also analyzed the distribution and quantity of PKA in limphoblastoid cell lines of the patient compared with a control; these experiments did not demonstrate any differences between the cell lines. Furthermore a collection of 98 DNA samples from sporadic Kallmann patients was screened for mutations in this gene. The analysis revealed two different sequence variations observed in two patients but not in 200 control chromosomes: since they have been detected also in the unaffected mother of one of the two patients we can assume that they are rare polymorphisms, although we cannot exclude that they represent mutations with incomplete penetrance. Our findings suggest that the complex phenotype with Kallmann syndrome and bone anomalies observed in our patient could be the result of the interruption of the AKAP2 gene. However, a position effect mediated by the translocation could not be excluded. The screening of AKAP2 in other Kallmann patients will be necessary to elucidate its role in the pathogenesis of the disease.
authors.affiliation: Laboratorio Genetica Medica, Ospedale S:Orsola Malpighi, Bologna, Italy. panza@med.unibo.it
authors.forename: Emanuele
authors.initials: E
authors.lastname: Panza
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gimelli
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.forename: Amnon
authors.initials: A
authors.lastname: Cohen
authors.forename: Stefania
authors.initials: S
authors.lastname: Gimelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.forename: Cristina
authors.initials: C
authors.lastname: Ghezzi
authors.forename: Bianca
authors.initials: B
authors.lastname: Sparatore
authors.forename: Babett
authors.initials: B
authors.lastname: Heye
authors.forename: Orsetta
authors.initials: O
authors.lastname: Zuffardi
authors.forename: Elena
authors.initials: E
authors.lastname: Rugarli
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
mesh_terms: D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D001847:Bone Diseases / Q000150:complications / Q000235:genetics*; D019457:Chromosome Breakage; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D017436:Kallmann Syndrome / Q000150:complications / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009833:Olfactory Pathways / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D054758:A Kinase Anchor Proteins; C484688:AKAP2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C111169:Pakap protein, mouse