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1.
Eur J Pediatr ; 169(3): 327-32, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19633868

ABSTRACT

Hereditary gingival fibromatosis (HGF) is a rare, clinically variable disorder characterized by slowly progressive fibrous overgrowth of the gingiva. Four gene loci have been mapped for autosomal dominant non-syndromic HGF (adHGF). The molecular basis of adHGF remains largely unknown, with only a single SOS1 gene mutation identified so far at the gingival fibromatosis 1 (GINGF1) locus in one family. We identified an adHGF family with ten affected individuals in whom onset of gingival fibromatosis concurred with the eruption of the primary teeth. In order to identify the molecular basis in this family, we tested for linkage of the disease to known adHGF loci. A maximal multipoint logarithm of the odds score of 3.91 was obtained with marker D2S390 (theta = 0) at the GINGF3 locus on chromosome 2p23.3-p22.3, and linkage to other known loci was excluded. Sequencing two candidate genes, ALK and C2orf18, and a single nucleotide polymorphisms array analysis did not reveal a mutation or copy number variation in a patient from the family. We refined the GINGF3 locus to a 6.56-cM, 8.27-Mb region containing 112 known and hypothetical genes, and our data and a search of the literature suggest that GINGF3 is a major adHGF locus.


Subject(s)
Fibromatosis, Gingival/genetics , Female , Fibromatosis, Gingival/pathology , Genetic Linkage , Genetic Loci , Humans , Male , Pedigree
2.
Eur J Hum Genet ; 17(9): 1154-9, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19259128

ABSTRACT

Duplication within the chromosome 17p11.2 (CMT1Adup), peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and gap junction beta1-protein (GJB1) gene mutations are frequent causes of the Charcot-Marie-Tooth disease (CMT). A large number of mutations in these genes are listed in databases. Sequence variants identified in patients are frequently reported as mutations without further evaluation. We analyzed 250 consecutively recruited unrelated Austrian CMT patients for CMT1Adup by microsatellite marker typing, real-time PCR or MLPA, and found 79 duplications (31.6%). The coding regions of the PMP22, MPZ and GJB1 genes were analyzed by direct sequencing in the remaining patients; 28 patients showed mutations, 14 of which were novel. We scored the pathogenicity of novel missense mutations by segregation studies and by their exclusion in control samples. Our comprehensive literature study found that up to 60% of the reported mutations in these genes had not been evaluated regarding their pathogenicity, and the PANTHER bioinformatics tool was used to score novel and published missense variants. The PANTHER program scored known polymorphisms as such, but scored approximately 82-88% only of the published and novel mutations as most likely deleterious. Mutations associated with axonal CMT were less likely to be classified as deleterious, and the PMP22 S72L mutation repeatedly associated with severe CMT was classified as a polymorphism using default parameters. Our data suggest that this in silico analysis tool could be useful for assessing the functional impact of DNA variations only as a complementary approach. The CMT1Adup, GJB1, MPZ and PMP22 mutation frequencies were in the range of those described in other CMT patient collectives with different ethnical backgrounds.


Subject(s)
Computational Biology/methods , Connexins/genetics , Mutation , Myelin P0 Protein/genetics , Myelin Proteins/genetics , Adolescent , Adult , Amino Acid Sequence , Austria , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/pathology , DNA Mutational Analysis , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Molecular Sequence Data , Sequence Homology, Amino Acid , Gap Junction beta-1 Protein
3.
Mol Imaging Biol ; 10(1): 24-9, 2008.
Article in English | MEDLINE | ID: mdl-18000714

ABSTRACT

PURPOSE: Friedreich ataxia (FRDA) is characterized by GAA expansions in the intron 1 of the frataxin gene correlating with disease onset and progression as well as cardiac affection. Accordingly, FRDA patients with early disease onset show a clear impairment of mitochondrial function in the myocardium. The purpose of this study was to investigate cardiac function and high-energy phosphate metabolism in FRDA patients with late disease onset. PROCEDURES: Using a 1.5 T magnetic resonance scanner, cardiac phosphorus-31 two-dimensional chemical shift imaging was performed in ten patients (seven male, three female) with a late onset of FRDA and in 35 healthy, male controls. Ejection faction (EF) and interventricular septum thickness (IST) were determined by echocardiography. RESULTS: The differences in left ventricular phosphocreatine (PCr) to beta-adenosine triphosphate (beta-ATP) ratios between both groups were not significant. FRDA patients had increased ISTs (10.8+/-1.6 vs. 9.7+/-0.9 mm; p=0.048), which correlated significantly with the left ventricular PCr to beta-ATP ratios (r= -0.644; p=0.04), and decreased EFs (52.24+/-7.72% vs. 64.09+/-4.25%; p=0.001) compared to normal controls. CONCLUSIONS: In contrast to FRDA patients with early disease onset, our patients collective exhibited a normal, probably compensated cardiac mitochondrial function, whereby IST and EF were mildly altered.


Subject(s)
Friedreich Ataxia/metabolism , Magnetic Resonance Imaging/methods , Myocardium/pathology , Adenosine Triphosphate/metabolism , Adult , Age of Onset , Demography , Female , Friedreich Ataxia/epidemiology , Heart Ventricles/metabolism , Heart Ventricles/pathology , Humans , Male , Phosphocreatine/metabolism , Phosphorus Isotopes
4.
Hum Genet ; 120(2): 285-92, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16847693

ABSTRACT

The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington's disease (HD) and determines 42-73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.


Subject(s)
Huntington Disease/epidemiology , Huntington Disease/genetics , Polymorphism, Genetic , Acyltransferases , Adaptor Proteins, Signal Transducing , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Child , Child, Preschool , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Huntingtin Protein , Huntington Disease/metabolism , Middle Aged , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nuclear Proteins/metabolism , Receptors, Kainic Acid/genetics , TATA-Box Binding Protein/genetics , TATA-Box Binding Protein/metabolism , GluK2 Kainate Receptor
5.
Eur J Nucl Med Mol Imaging ; 33(9): 1084-90, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16699769

ABSTRACT

PURPOSE: The purpose of this study was to investigate the monoamine transporter status of dopamine, serotonin and norepinephrine throughout the brain in spinocerebellar ataxia type 2 (SCA2). To this end, nine patients were studied with [(123)I]beta-CIT SPECT. METHODS: Data were compared with ten age-matched healthy control subjects and ten patients with young-onset Parkinson's disease (YOPD), matched for age. Parametric SPECT images of the specific-to-non-displaceable equilibrium partition coefficient (V (3)''), which is proportional to the receptor density (B (max)), were generated. In order to objectively localise focal changes in beta-CIT uptake throughout the brain volume without having to make an a priori hypothesis as to their location, statistical parametric mapping (SPM) was applied to SPECT images. Data clusters revealed by SPM, showing significant differences in V (3)'' values between groups, were transformed onto the individual V (3)'' image to obtain mean regional uptake values. RESULTS: Both SCA2 and YOPD patients showed significant decreases in striatal [(123)I]beta-CIT SPECT uptake when compared with controls. However, in SCA2 patients, additional reductions in caudate/anterior putamen, midbrain and pons [(123)I]beta-CIT uptake were localised with SPM. CONCLUSION: Voxel-wise analysis of [(123)I]beta-CIT SPECT revealed more widespread decline of monoamine transporter availability in SCA2 than in YOPD, reflecting differences in the underlying pathology. We suggest that the quantification of midbrain and pons [(123)I]beta-CIT signal is likely to improve the diagnostic accuracy in patients presenting with clinical features of both SCA2 and YOPD at initial investigation.


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Mutation , Nerve Tissue Proteins/genetics , Spinocerebellar Ataxias/diagnostic imaging , Spinocerebellar Ataxias/metabolism , Vesicular Monoamine Transport Proteins/metabolism , Adult , Ataxins , Case-Control Studies , Cocaine/analogs & derivatives , Female , Humans , Iodine Radioisotopes , Male , Middle Aged , Radiopharmaceuticals , Spinocerebellar Ataxias/genetics , Tomography, Emission-Computed, Single-Photon
6.
Mov Disord ; 21(7): 1043-7, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16570300

ABSTRACT

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder that results from an expanded trinucleotide (CAG) repeat on the huntingtin gene. Neurodegeneration in HD affects most prominently the basal ganglia. Therefore, diffusivity was obtained in the basal ganglia and thalamus of 29 patients with early HD and 27 healthy volunteers by means of the trace of the diffusion tensor (Trace(D)). Putaminal, caudate, pallidal, and thalamic Trace(D) values were increased in patients with HD compared with controls. Increased diffusivity in the putamen and caudate nucleus correlated with global functional impairment, CAG repeat length, as well as bicaudate ratio. Diffusion-weighted imaging appears to be a promising surrogate marker for disease severity in HD. Sensitivity to change remains to be established longitudinally.


Subject(s)
Diffusion Magnetic Resonance Imaging , Huntington Disease/diagnosis , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Activities of Daily Living/classification , Adult , Aged , Basal Ganglia/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Reference Values , Severity of Illness Index , Thalamus/pathology
7.
Neurogenetics ; 7(1): 27-30, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16369839

ABSTRACT

An expanded polyglutamine stretch in the huntingtin protein has been identified as the pathogenetic cause of Huntington's disease (HD). Although the length of the expanded polyglutamine repeat is inversely correlated with the age-at-onset, additional genetic factors are thought to modify the variance in the disease onset. As linkage analysis suggested a modifier locus on chromosome 4p, we investigated the functional relevance of S18Y polymorphism of the ubiquitin carboxy-terminal hydrolase L1 in 946 Caucasian HD patients. In this group, the allelic variation on locus S18Y is responsible for 1.1% of the variance in the HD age-at-onset, and the rare Y allele is associated with younger-aged cases.


Subject(s)
Huntington Disease/genetics , Nerve Tissue Proteins/genetics , Nuclear Proteins/genetics , Polymorphism, Genetic , Ubiquitin Thiolesterase/genetics , Age of Onset , Humans , Huntingtin Protein , Huntington Disease/physiopathology , Trinucleotide Repeats
8.
Mov Disord ; 19(11): 1320-5, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15390003

ABSTRACT

Extrapyramidal features may occur in spinocerebellar ataxias consistent with neuropathological evidence of nigrostriatal involvement. Recently, striatal dopaminergic neurotransmission was found to be abnormal in the uncommon parkinsonian presentation of spinocerebellar ataxia type 2 (SCA2). We have investigated, therefore, striatal dopamine transporter and D2 receptor function in a series of 9 patients with the more common ataxic presentation of SCA2 using single photon emission computed tomography and beta-CIT as well as IBZM. Age-matched healthy subjects and patients with Parkinson's disease (PD) served as controls. All except 1 SCA2 patient exhibited slowness of limb movements without rigidity or rest tremor. In addition, cervical dystonia was present in 5 and dystonic head tremor in 2 SCA2 patients. Striatocerebellar (S/C) ratios of beta-CIT binding were significantly reduced in SCA2 patients compared to control subjects, and they were within the range of PD patients. S/C ratios of IBZM binding were significantly reduced in SCA2 patients compared to control subjects. We conclude that dopaminergic neurotransmission is impaired in the ataxic presentation of SCA2, with a prominent loss of striatal dopamine transporter function. Both slowness of limb movements as well as dystonia in the ataxic SCA2 phenotype may reflect dysfunction not only at cerebellar but also at basal ganglia level.


Subject(s)
Cocaine/analogs & derivatives , Membrane Glycoproteins/physiology , Membrane Transport Proteins/physiology , Nerve Tissue Proteins/physiology , Receptors, Dopamine D2/physiology , Spinocerebellar Ataxias/diagnostic imaging , Synaptic Transmission/physiology , Tomography, Emission-Computed, Single-Photon/methods , Adult , Basal Ganglia/diagnostic imaging , Basal Ganglia/physiopathology , Benzamides , Cerebellum/diagnostic imaging , Cerebellum/physiopathology , Dopamine Plasma Membrane Transport Proteins , Dystonic Disorders/diagnostic imaging , Dystonic Disorders/physiopathology , Female , Humans , Iodine Radioisotopes , Male , Middle Aged , Parkinson Disease/diagnostic imaging , Parkinson Disease/physiopathology , Parkinsonian Disorders/diagnostic imaging , Parkinsonian Disorders/physiopathology , Pyrrolidines , Reference Values , Spinocerebellar Ataxias/physiopathology
9.
J Hepatol ; 38(2): 164-8, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12547404

ABSTRACT

BACKGROUND: Non-Wilsonian hepatic copper toxicosis includes Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETIC) and the non-Indian disease known as idiopathic copper toxicosis (ICT). These entities resemble the hepatic copper overload observed in livers of Bedlington terriers with respect to their clinical presentation and biochemical and histological findings. We recently cloned the gene causing copper toxicosis in Bedlington terriers, MURR1, as well as the orthologous human gene on chromosome 2p13-p16. AIM: To study the human orthologue of the canine copper toxicosis gene as a candidate gene for ICC, ETIC, and ICT. METHODS: We sequenced the exons and the intron-exon boundaries of the human MURR1 gene in 12 patients with classical ICC, one patient with ETIC, and 10 patients with ICT to see whether these patients display any mutations in the human orthologue of the canine copper toxicosis gene. RESULTS: No mutations in the MURR1 gene, including the intron-exon boundaries, were identified in a total of 23 patients with non-Wilsonian hepatic copper toxicosis. CONCLUSIONS: Our results demonstrate that copper toxicosis in Bedlington terriers is not an animal model for the non-Wilsonian hepatic copper toxicosis described in this study.


Subject(s)
Copper/adverse effects , Liver Cirrhosis/genetics , Metabolism, Inborn Errors/genetics , Proteins/genetics , Adaptor Proteins, Signal Transducing , Animals , Base Sequence , Carrier Proteins , Copper/metabolism , Dogs , Hepatolenticular Degeneration , Humans , Infant , Molecular Sequence Data
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