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FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2007 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 3, 379-382 p.Article in journal (Refereed) Published
Abstract [en]

Aplasia of lacrimal and salivary glands (ALSG) is an autosomal dominant congenital anomaly characterized by aplasia, atresia or hypoplasia of the lacrimal and salivary systems. Affected individuals present with irritable eyes and dryness of the mouth with variable expressivity. Mutations in FGF10 were recently described in ALSG and in lacrimo-auriculo-dento-digital (LADD) syndrome which are overlapping clinical entities. We present here two families with ALSG associated with missense mutations (R80S and G138E, respectively) affecting highly conserved residues in FGF10. The clinical features of these patients further broaden the knowledge of FGF10-related phenotypes.

Place, publisher, year, edition, pages
2007. Vol. 15, no 3, 379-382 p.
Keyword [en]
ALSG, LADD syndrome, FGF10, missense mutations
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-16743DOI: 10.1038/sj.ejhg.5201762ISI: 000244406200019PubMedID: 17213838OAI: oai:DiVA.org:uu-16743DiVA: diva2:44514
Available from: 2008-06-03 Created: 2008-06-03 Last updated: 2011-02-11Bibliographically approved
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 448
National Category
Medical Genetics
Research subject
Clinical Genetics
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)
Available from: 2009-04-24 Created: 2009-04-02 Last updated: 2009-04-24Bibliographically approved

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