| 1. |
- Baranowska Körberg, Izabella, et al.
(författare)
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A progressive and complex clinical course in two family members with ERF-related craniosynostosis: a case report
- 2020
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. Case presentation Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. Conclusions Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.
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| 2. |
- Baranowska Körberg, Izabella, et al.
(författare)
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A Simple Repeat Polymorphism in the MITF-M Promoter Is a Key Regulator of White Spotting in Dogs
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e104363-
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Tidskriftsartikel (refereegranskat)abstract
- The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (s(w)). We have investigated four candidate mutations associated with the s(w) allele, a SINE insertion, a SNP at a conserved site and a simple repeat polymorphism all associated with the MITF-M promoter as well as a 12 base pair deletion in exon 1B. The variants associated with white spotting at all four loci were also found among wolves and we conclude that none of these could be a sole causal mutation, at least not for extreme white spotting. We propose that the three canine white spotting alleles are not caused by three independent mutations but represent haplotype effects due to different combinations of causal polymorphisms. The simple repeat polymorphism showed extensive diversity both in dogs and wolves, and allele-sharing was common between wolves and white spotted dogs but was non-existent between solid and spotted dogs as well as between wolves and solid dogs. This finding was unexpected as Solid is assumed to be the wild-type allele. The data indicate that the simple repeat polymorphism has been a target for selection during dog domestication and breed formation. We also evaluated the significance of the three MITF-M associated polymorphisms with a Luciferase assay, and found conclusive evidence that the simple repeat polymorphism affects promoter activity. Three alleles associated with white spotting gave consistently lower promoter activity compared with the allele associated with solid colour. We propose that the simple repeat polymorphism affects cooperativity between transcription factors binding on either flanking sides of the repeat. Thus, both genetic and functional evidence show that the simple repeat polymorphism is a key regulator of white spotting in dogs.
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| 3. |
- Baranowska Körberg, Izabella, et al.
(författare)
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Clinical characteristics of epilepsy of unknown origin in the Rottweiler breed
- 2015
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Ingår i: Acta Veterinaria Scandinavica. - : Springer Science and Business Media LLC. - 0044-605X .- 1751-0147. ; 57
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epilepsy is one of the most common neurological conditions in dogs. Despite that epilepsy appears to be common in the Rottweiler breed, published literature about the phenotype of epilepsy in this breed is lacking. The aim of this questionnaire-based study was to describe the clinical characteristics of epilepsy in the Rottweiler breed including; signalment, pedigree, housing conditions and information about the seizures such as age at onset, seizure type, duration, and progression, as well as number of seizure days (24 h), effect and side effects of anti-epileptic drugs, and potential comorbidities. The diagnosis for epilepsy of unknown origin was based on the following inclusion criteria: >= 2 seizure days, starting between 6 months and 7 years of age, no known history of poisoning or serious head trauma, and (when available), pre-study routine serum biochemical parameters were within the reference intervals.Results: A total of 37 cases (23 females and 14 males) were included in the study. The median age at onset of seizures was 36 months (range 8-84 months). The dogs suffered from generalized tonic-clonic seizures, and more than 50 % of the dogs had experienced cluster seizures (>1 seizure in 24 h). The dogs commonly started to seizure while resting (23/36) and/or sleeping (20/36). Only 3 of the 36 dogs experienced seizures during activities such as walking or training. All of the 24/37 (64.9 %) dogs on antiepileptic drugs received phenobarbital. Five dogs needed addon treatment (n = 5), and of these: one dog was on 3 drugs (phenobarbital, potassium bromid and levetiracetam) (n = 1), three dogs were on phenobarbital and potassium bromide (n = 3), and one dog received phenobarbital and imepitoin (n = 1). Seizure frequency did not necessarily improve following antiepileptic treatment, and for six of 21 (28.6 %) of the dogs, seizure frequency increased. All of the Rottweilers in this study had relatives with epilepsy reported.Conclusions: The Rottweilers suffering from epilepsy in this study presented with generalized tonic-clonic seizures, and their response to antiepileptic treatment was variable. More than 50 % of the dogs had experienced cluster seizures (>1 seizure in 24 h).
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| 4. |
- Baranowska Körberg, Izabella
(författare)
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Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70x10(-10), OR = 3.3). Fine mapping study defined a similar to 1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7x10(-8), OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28x10(-11), OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.
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| 5. |
- Baranowska Körberg, Izabella
(författare)
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Inherited Polyneuropathy in Leonberger Dogs
- 2011
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Ingår i: Journal of Veterinary Internal Medicine. - : Wiley. - 0891-6640 .- 1939-1676. ; 25, s. 997-1002
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Tidskriftsartikel (refereegranskat)abstract
- Conclusions and Clinical Importance: The ILPN is considered most likely to be one disease, and the inheritance of ILPN is best explained by an underlying X-linked mode of transmission for the phenotype. However, age at onset and severity of signs might be determined by contributing loci. This has consequences in molecular genetic studies and for breeding strategies aimed at eliminating this disease.
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| 6. |
- Baranowska Körberg, Izabella
(författare)
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Mapping trait genes in dogs : using the dog as a model organism
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Understanding the genetic background of a given phenotypic trait or disease has long intrigued scientists. Model organisms can be employed when it is not feasible or possible to find trait causality in human cohorts. This thesis reports the mapping of both a phenotypic trait (white spotting) and a disease (sensory ataxic neuropathy) in dogs, and in doing so highlights the potential of the dog as a model organism for mapping traits of relevance to human health and biology. For white spotting, a two-stage mapping approach was used to identify an associated genomic region, which contained only the microphtalmia-associated transcription factor (MITF) gene. Stage 1: a genome-wide association analysis in a single breed, taking advantage of the extensive within breed linkage disequilibrium (LD) and long haplotypes, identified a discrete region of approximately 1 Mb. Stage 2: finemapping in an additional breed presenting the same phenotype, exploiting the short LD and haplotypes shared across dog breeds, was used to narrow the region to about 100 kb. We functionally evaluated two candidate polymorphisms associated with MITF, a SINE insertion and a length polymorphism upstream of the melanocyte-specific transcription start site of MITF. The data indicated that both polymorphisms affect transcription from the MITF-M promoter. Sensory ataxic neuropathy (SAN) is a neurological disorder affecting a specific maternal lineage of Golden Retrievers. We identified a one base pair deletion in mitochondrial tRNATyr and through biochemical analyses of mitochondria and functional studies of the deletion, confirmed causality and the mitochondrial origin of SAN. This is one of the first mitochondrial disorders identified in dogs and we additionally developed a genetic test for the public to allow for the elimination of the disease from this breed. The genetic and functional analyses of both white spotting coat colour and SAN in dogs, which are controlled by mutations of the two different genomes, clearly demonstrate the utility of the canine model and establish a new role for man's best friend.
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| 7. |
- Lundin, Johanna, et al.
(författare)
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Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene
- 2019
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Ingår i: Molecular Genetics and Genomic Medicine. - : Wiley. - 2324-9269. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: The bladder exstrophy-epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases. Methods: We performed array comparative genomic hybridization (array-CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies. Results: We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10−4). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1wt and Lztr1mut, indicating a potential functional effect of the LZTR1mut. Conclusion: Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation.
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