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Mutations in the gene encoding fibroblast growth factor 10 are associated with
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.ORCID iD: 0000-0003-4185-7409
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2005 (English)In: Nat Genet, ISSN 1061-4036, Vol. 37, no 2, 125-7 p.Article in journal (Refereed) Published
Abstract [en]

Autosomal dominant aplasia of lacrimal and salivary glands (ALSG; OMIM 180920 and OMIM 103420) is a rare condition characterized by irritable eyes and dryness of the mouth. We mapped ALSG to 5p13.2-5q13.1, which coincides with the gene fibroblast growth factor 10 (FGF10). In two extended pedigrees, we identified heterozygous mutations in FGF10 in all individuals with ALSG. Fgf10(+/-) mice have a phenotype similar to ALSG, providing a model for this disorder. We suggest that haploinsufficiency for FGF10 during a crucial stage of development results in ALSG.

Place, publisher, year, edition, pages
2005. Vol. 37, no 2, 125-7 p.
Keyword [en]
Animals, Base Sequence, Chromosomes; Human; Pair 5, Fibroblast Growth Factors/*genetics, Genes; Dominant, Heterozygote, Humans, Lacrimal Apparatus/*abnormalities, Mice, Molecular Sequence Data, Mutation, Pedigree, Research Support; Non-U.S. Gov't, Salivary Glands/*abnormalities
Identifiers
URN: urn:nbn:se:uu:diva-73178PubMedID: 15654336OAI: oai:DiVA.org:uu-73178DiVA: diva2:101089
Available from: 2005-09-20 Created: 2005-09-20 Last updated: 2016-02-29
In thesis
1. Molecular Genetic Studies of ALSG, Kostmann Syndrome and a Novel Chromosome 10 Inversion
Open this publication in new window or tab >>Molecular Genetic Studies of ALSG, Kostmann Syndrome and a Novel Chromosome 10 Inversion
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In summary, this thesis presents the localisation and identification of genetic variants of which some are disease associated and some considered to be neutral. Knowledge of the basic mechanisms behind human disorders is important both from a biological and medical point of view.

The thesis is based on four papers of which the first two clarify the genetic basis of autosomal dominant aplasia of lacrimal and salivary glands (ALSG). ALSG is a rare disorder with high penetrance and variable expressivity characterized by dry mouth and eyes. In paper I, we located the ALSG gene to a 22 centiMorgan region on chromosome 5 through a genome-wide linkage scan with microsatellite markers in two families. Mutations were found in the gene encoding fibroblast growth factor 10 (FGF10) situated in the linked chromosome 5 region. Mice having only one copy of the FGF10 gene (Fgf10+/- mice) have a phenotype similar to ALSG, providing an animal model for the disorder. In paper II, we describe two additional patients with ALSG and missense mutations in FGF10, providing further genotype-phenotype correlations.

The aim of paper III was to identify a gene involved in autosomal recessive severe congenital neutropenia (SCN), also referred to as Kostmann syndrome. The disease is characterized by a very low absolute neutrophil count and recurrent bacterial infections. Affected individuals from the family with SCN originally described by Dr Kostmann were genotyped with whole-genome SNP arrays. Autozygosity mapping identified a shared haplotype spanning 1.2 Mb on chromosome 1q22. This region contained 37 known genes, of which several were associated with myelopoiesis. Our finding contributed to the identification of the gene mutated in Kostmann syndrome.

In paper IV a cytogenetic inversion on chromosome 10 was mapped and characterized. Sequence- and haplotype analysis of carriers from four non-related Swedish families revealed identical inversion breakpoints and established that the rearrangement was identical by descent. A retrospective study of karyotypes together with screening of large sample sets established that the inversion is a rare and inherited chromosome variant with a broad geographical distribution in Sweden. No consistent phenotype was found associated with the inversion.

Genetic research increases the understanding of our genomes and makes it possible to discover variants contributing to disease. Identification of such genetic variants further enables studies of gene function and pathogenesis. The finding of the disease associated variants in this thesis will eventually contribute to improved diagnosis, prognosis, risk assessment and a future treatment of patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 448
Series
National Category
Medical Genetics
Research subject
Clinical Genetics
Identifiers
urn:nbn:se:uu:diva-100598 (URN)978-91-554-7493-5 (ISBN)
Public defence
2009-05-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-24 Created: 2009-04-02 Last updated: 2009-04-24Bibliographically approved

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Entesarian, MiriamMatsson, HansKlar, JoakimDahl, Niklas

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