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Frykholm, Carina
Publications (8 of 8) Show all publications
Zhao, J. J., Halvardson, J., Zander, C., Zaghlool, A., Georgii-Hemming, P., Månsson, E., . . . Feuk, L. (2018). Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 177(1), 10-20
Open this publication in new window or tab >>Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability
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2018 (English)In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 177, no 1, p. 10-20Article in journal (Refereed) Published
Abstract [en]

Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-326280 (URN)10.1002/ajmg.b.32574 (DOI)000417876700002 ()28990276 (PubMedID)
Funder
EU, European Research Council
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-17Bibliographically approved
Frykholm, C., Klar, J., Tomanovic, T., Ameur, A. & Dahl, N. (2018). Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype. European Journal of Human Genetics, 26(12), 1871-1874
Open this publication in new window or tab >>Stereocilin gene variants associated with episodic vertigo: expansion of the DFNB16 phenotype
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2018 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 12, p. 1871-1874Article in journal (Refereed) Published
Abstract [en]

Vestibular disorders comprise a heterogeneous group of diseases with transient or permanent loss of vestibular function. Vestibulopathy is in most cases associated with migraine, Meniere disease, hereditary ataxias, or sensorineural hearing loss. We identified two brothers and their first cousin affected by hearing loss and episodic vertigo. The brothers were homozygous STRC nonsense variant [c.4027 C> T, p.(Q1343*)], whereas their first cousin was compound heterozygous for the STRC nonsense variant and a 97 kb deletion spanning the entire STRC gene. Clinical investigations confirmed pathological vestibular responses in addition to a characteristic DFNB16 hearing loss. The STRC gene encodes Stereocilin in the cochlea and in the vestibular organ where it ensheathes the kinocilium of the otolithic membranes. Stereocilin is associated with the gel overlaying the vestibular kinocilia, suggesting a role for the protein in sensing balance and spatial orientation. Our findings support such a function for Stereocilin in the vestibular organ and expand the phenotype associated with DFNB16.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:uu:diva-371126 (URN)10.1038/s41431-018-0256-6 (DOI)000450614800019 ()30250054 (PubMedID)
Funder
Swedish Research Council, 2015-02424The Swedish Brain FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-12-20 Created: 2018-12-20 Last updated: 2018-12-20Bibliographically approved
Bondeson, M.-L., Ericson, K., Gudmundsson, S., Ameur, A., Ponten, F., Wesström, J., . . . Wilbe, M. (2017). A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.. Clinical Genetics, 92(5), 510-516
Open this publication in new window or tab >>A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.
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2017 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 92, no 5, p. 510-516Article in journal (Refereed) Published
Abstract [en]

Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.

Keywords
CEP55, Meckel-like, ciliopathy, cytokinesis, whole exome sequencing
National Category
Clinical Medicine Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-318127 (URN)10.1111/cge.13012 (DOI)000412590300007 ()28295209 (PubMedID)
Funder
Magnus Bergvall FoundationLars Hierta Memorial FoundationSwedish Society for Medical Research (SSMF)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2019-01-04Bibliographically approved
Wilbe, M., Gudmundsson, S., Johansson, J., Ameur, A., Stattin, E.-L., Annerén, G., . . . Bondeson, M.-L. (2017). A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders. Prenatal Diagnosis, 37(11), 1146-1154
Open this publication in new window or tab >>A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
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2017 (English)In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 37, no 11, p. 1146-1154Article in journal (Refereed) Published
Abstract [en]

Objective

De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred.

Methods

We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction.

Results

In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk.

Conclusions

Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-342916 (URN)10.1002/pd.5156 (DOI)000415897200012 ()28921562 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2019-03-17Bibliographically approved
Storm, T., Tranebjærg, L., Frykholm, C., Birn, H., Verroust, P. J., Nevéus, T., . . . Nielsen, R. (2013). Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration. Nephrology, Dialysis and Transplantation, 28(3), 585-591
Open this publication in new window or tab >>Renal phenotypic investigations of megalin-deficient patients: novel insights into tubular proteinuria and albumin filtration
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2013 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 28, no 3, p. 585-591Article in journal (Refereed) Published
Abstract [en]

Background

The reabsorption of filtered plasma proteins, hormones and vitamins by the renal proximal tubules is vital for body homeostasis. Studies of megalin-deficient mice suggest that the large multi-ligand endocytic receptor megalin plays an essential role in this process. In humans, dysfunctional megalin causes the extremely rare Donnai-Barrow/Facio-Oculo-Acustico-Renal (DB/FOAR) syndrome characterized by a characteristic and multifaceted phenotype including low-molecular-weight proteinuria. In this study, we examined the role of megalin for tubular protein reabsorption in humans through analysis of proximal tubular function in megalin-deficient patients.

Methods

Direct sequencing of the megalin-encoding gene (LRP2) was performed in a family in which three children presented with classical DB/FOAR manifestations. Renal consequences of megalin deficiency were investigated through immunohistochemical analyses of renal biopsy material and immunoblotting of urine samples.

Results

In the patients, a characteristic urinary protein profile with increased urinary excretion of vitamin D-binding protein, retinol-binding protein and albumin was associated with absence of, or reduced, proximal tubular endocytic uptake as shown by renal immunohistochemistry. In the absence of tubular uptake, urinary albumin excretion was in the micro-albuminuric range suggesting that limited amounts of albumin are filtered in human glomeruli.

Conclusions

This study demonstrated that megalin plays an essential role for human proximal tubular protein reabsorption and suggests that only limited amounts of albumin is normally filtered in the human glomeruli. Finally, we propose that the characteristic urinary protein profile of DB/FOAR patients may be utilized as a diagnostic marker of megalin dysfunction.

National Category
Clinical Laboratory Medicine Basic Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-183402 (URN)10.1093/ndt/gfs462 (DOI)000316120000015 ()23048173 (PubMedID)
Available from: 2012-10-25 Created: 2012-10-25 Last updated: 2018-01-12
Storm, T., Nielsen, R., Christensen, E., Frykholm, C., Tranebjaerg, L., Birn, H., . . . Ericson, K. (2012). Renal consequences of megalin deficiency in humans. Paper presented at 49th Congress of the European-Renal-Association/European-Dialysis-and-Transplant-Association (ERA-EDTA), MAY 24-27, 2012, Paris, FRANCE. Nephrology, Dialysis and Transplantation, 27(S2), 326-327
Open this publication in new window or tab >>Renal consequences of megalin deficiency in humans
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2012 (English)In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 27, no S2, p. 326-327Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-190848 (URN)000311494701101 ()
Conference
49th Congress of the European-Renal-Association/European-Dialysis-and-Transplant-Association (ERA-EDTA), MAY 24-27, 2012, Paris, FRANCE
Available from: 2013-01-09 Created: 2013-01-08 Last updated: 2019-02-01Bibliographically approved
Klar, J., Frykholm, C., Friberg, U. & Dahl, N. (2006). A Meniere's disease gene linked to chromosome 12p12.3.. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 141B(5), 463-467
Open this publication in new window or tab >>A Meniere's disease gene linked to chromosome 12p12.3.
2006 (English)In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 141B, no 5, p. 463-467Article in journal (Refereed) Published
Abstract [en]

Meniere's disease (MD) is characterized by spontaneous attacks of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. The majority of patients with MD appear sporadic but 5%–13% of the cases have a family history for the disease. The cause of both the sporadic and inherited forms of MD remains unclear despite a number of candidate genes defined from their association with hearing loss. We have performed a genome wide linkage scan on a large Swedish family segregating MD in five generations. Five candidate regions with a lod score of >1 were identified. Two additional families with autosomal dominant MD were analyzed for linkage to these regions and a cumulative Zmax of 3.46 was obtained for a single region on chromosome 12p. In two of the three families, a shared haplotype was found to extend over 1.7 Mb which suggests a common ancestral origin. Within this region, a single recombination event restricts the candidate region to 463 kb.

Keywords
1-Phosphatidylinositol 3-Kinase/genetics, Chromosome Mapping/*methods, Chromosomes; Human; Pair 12/*genetics, Family Health, Female, Genetic Predisposition to Disease/genetics, Genotype, Haplotypes, Humans, Linkage (Genetics), Lod Score, Male, Meniere Disease/*genetics, Microsatellite Repeats/genetics, Pedigree, Protein Subunits/genetics
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-15551 (URN)10.1002/ajmg.b.30347 (DOI)16741942 (PubMedID)
Available from: 2008-02-20 Created: 2008-02-20 Last updated: 2017-12-08Bibliographically approved
Frykholm, C., Larsen, H.-C., Dahl, N., Klar, J. & Friberg, U. (2006). Familial Meniere's disease in five generations. Otology and Neurotology, 27(5), 681-686
Open this publication in new window or tab >>Familial Meniere's disease in five generations
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2006 (English)In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 27, no 5, p. 681-686Article in journal (Refereed) Published
Abstract [en]

Objective: Clinical characterization of a Swedish family followed for five generations. Several members of each generation had Meniere's disease (MD). Possible modes of genetic transmission were assessed.

Study Design: Retrospective family survey.

Setting: University hospital. Tertiary referral center.

Patients: Members of a large family in which several members in each generation were affected by MD.

Interventions: Hearing levels were assessed, and the patients were asked to complete a questionnaire regarding age at onset, hearing loss, tinnitus, aural fullness, vertigo, and if MD was unilateral or bilateral. Glycerol tests were performed in a few cases. For deceased relatives, information was obtained from patient charts and interviews with relatives. Genetic studies with linkage analysis was performed for the loci DFNA 1, DFNA6/14, DFNA9, and DFNA 15.

Results: One member of Generation I and, according to patient charts, two members of Generation 11 could have suffered from MD. In Generations III to V, 9 of 25 members developed inner ear dysfunction. Six of these individuals developed MD that was strictly in accordance with American Academy of Otolaryngology and Head and Neck Surgery, 1995 guidelines criteria, whereas three individuals had unilateral or bilateral hearing impairment, one in combination with benign paroxysmal positioning vertigo, which could represent an incomplete expression of the disease. ne mean age at disease onset was 64.5 years in Generation 111, 43 years in Generation W, and 25 years in Generation V. In the genetic studies, none of the regions investigated showed linkage to the disease gene with a significant calculated log of odds ratio (LOD) score above three.

Conclusion: The pattern of inheritance suggested that familial MD was autosomal dominant and exhibited incomplete expression of inner ear symptoms in some affected members. The decreasing age at onset of disease with succeeding generations could indicate anticipation. None of the hitherto-known DFNA loci, which has phenotypes hearing some resemblance to MD, had haplotypes in common with this large family affected by MD.

Keywords
anticipation, cochleovestibular dysfunction, familial, Meniere's disease
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-96366 (URN)10.1097/01.mao.0000226315.27811.c8 (DOI)000239528500019 ()16868516 (PubMedID)
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2017-12-14Bibliographically approved
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