Biomedical subjects

Niklas Dahl

Publications and source records attributed to Niklas Dahl.

At least 19 recordsLinked to original sources

PubMed2007

FGF10 missense mutations in aplasia of lacrimal and salivary glands (ALSG).

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.

Amino Acid Sequence↗

PubMed2006

HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).

Autosomal recessive severe congenital neutropenia (SCN) constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells, yet the underlying genetic defect remains unknown. Using a positional cloning approach and candidate gene evaluation, we identified a recurrent homozygous germline mutation in HAX1 in three pedigrees. After further molecular screening of individuals with SCN, we identified 19 additional affected individuals with homozygous HAX1 mutations, including three belonging to the original pedigree described by Kostmann. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction and cytoskeletal control. Here, we show that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Our findings suggest that HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Adult-onset autosomal dominant leukodystrophy with autonomic symptoms restricted to 1.5 Mbp on chromosome 5q23.

Autosomal dominant leukodystrophy (ADLD) with autonomic symptoms is a slowly progressive leukodystrophy with an onset in the 4th to 6th decade of life. Early symptoms are derived from the autonomic nervous system with bladder dysfunction in the majority of patients. The disease progresses slowly with loss of fine motor skills, ataxia, and affected individuals may survive for two decades after onset of symptoms. The molecular basis behind ADLD remains unknown but the causative locus was previously mapped to a 4 cM region on chromosome 5. We have recently identified a large family of Swedish origin with this type of ADLD. Linkage analysis on samples from family members confirmed linkage to 5q23 and supports genetic homogeneity for the disease. We fine mapped and localized the ADLD gene to a 0.96 cM region between D5S1495 and CTT/CCT15. A maximum parametric multipoint location score of 9.45 was obtained for a position at the marker CTT55. From our results we conclude that the ADLD gene locus is restricted to a 1.47 Mbp interval containing 13 known or putative genes.

Adult↗

PubMed2006

A Meniere's disease gene linked to chromosome 12p12.3.

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 Z(max) 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.

Chromosome Mapping↗

PubMed2006

Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation.

We report a young boy with penoscrotal hypospadias, anal atresia (AA) with a recto-urethral fistula, a hypoplastic kidney and a balanced translocation t(6;17)(p21.31;q11.2). Physical mapping of the breakpoints localized the chromosome 6 breakpoint within an intron of the gene lipoma HMGIC fusion partner-like 5 (LHFPL5) whereas the chromosome 17 breakpoint was mapped to the first intron of the 182-FIP gene encoding the Fragile X Mental Retardation Protein Interacting Protein. Sequence analysis across the breakpoints revealed an almost perfectly balanced translocation with a 2 bp deletion on the derivative chromosome 6 and a 7 bp duplication on the derivative chromosome 17. We identified a fusion transcript consisting of the first exon of 182-FIP and the last exon of LHFPL5 in patient-derived cells. Quantitative expression analysis of the genes flanking the breakpoints, revealed increased transcript levels for SFRS protein kinase 1 (SRPK1) and TAO kinase 1 (TAOK1) which suggests a positional effect due to the translocation. We hypothesize that the urogenital and anorectal malformations in the patient result from one or several mechanisms including disruption of the genes 182-FIP and LHFPL5, altered expression of the genes flanking the translocation breakpoints and, a gain of function mechanism mediated by the 182-FIP-LHFPL5 fusion transcript.

Abnormalities, Multiple↗

PubMed2006

Variant phenotype of Best vitelliform macular dystrophy associated with compound heterozygous mutations in VMD2.

PURPOSE: To characterize the phenotype of members of a Swedish family with Best macular dystrophy and two distinct mutations in VMD2. METHODS: Venous blood samples were obtained from six family members and screened for mutations in VMD2. Six individuals were examined clinically, four of whom were further investigated with full-field electroretinography (ERG), electro-oculography (EOG), multifocal electroretinography (mfERG), and optical coherence tomography (OCT). RESULTS: The VMD2 mutations resulting in Arg141His and Tyr29stop were identified in family members. Two individuals harbored both mutations, one mutation in each VMD2 allele. These two family members had an abnormal EOG and their full-field ERG demonstrated widespread degeneration with a prolonged implicit time in the cone 30-Hz flicker ERG. MfERG verified reduction of the central retinal function and OCT demonstrated intraretinal fluid, swelling, and thickening of the outer retina-RPE-choroid complex (ORCC). CONCLUSION: A previously undescribed severe form of Best macular dystrophy is associated with compound heterozygous mutations in VMD2.

Adult↗

PubMed2006

Familial Ménière's disease in five generations.

OBJECTIVE: Clinical characterization of a Swedish family followed for five generations. Several members of each generation had Ménière'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 DFNA15. RESULTS: One member of Generation I and, according to patient charts, two members of Generation II 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. The mean age at disease onset was 64.5 years in Generation III, 43 years in Generation IV, 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 bearing some resemblance to MD, had haplotypes in common with this large family affected by MD.

Adult↗

PubMed2005

Mutations in the gene encoding fibroblast growth factor 10 are associated with aplasia of lacrimal and salivary glands.

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.

Animals↗

PubMed2005

RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity.

We have identified a family comprising a mother and two children with idiopathic and profound obesity body mass index (BMI) 41-49 kg/m(2). The three family members carry a balanced reciprocal chromosome translocation t(4;15). We present here the clinical features of the affected individuals as well as the physical mapping and cloning of the chromosomal breakpoints. A detailed characterisation of the chromosomal breakpoints at chromosomes 4 and 15 revealed that the translocation is almost perfectly balanced with a very short insertion/deletion. The chromosome 15 breakpoint is positioned in intron 1 of the RAR-related orphan receptor A isoform 1 (RORa1) and the chromosome 4 breakpoint is positioned 133 kb telomeric to the transcriptional start of the unc-5 homolog B (UNC5C) and 154 kb centromeric of the transcriptional start of the pyruvate dehydrogenase (lipoamide) alpha 2 (PDHA2). The rearrangement creates a fusion gene, which includes the RORa1 exon 1 and UNC5C that is expressed in frame in adipocytes from the affected patients. We also show that this transcript is translated into a protein. From previous reports, it is shown that RORa1 is implicated in the regulation of adipogenesis and lipoprotein metabolism. We hypothesise that the obesity in this family is caused by (i) haploinsufficiency for RORa1 or, (ii) a gain of function mechanism mediated by the RORa1-UNC5C fusion gene.

Adipocytes↗

PubMed2005

Loss of ZDHHC15 expression in a woman with a balanced translocation t(X;15)(q13.3;cen) and severe mental retardation.

X-linked mental retardation (XLMR) affects one in 600 males and is highly heterogeneous. We describe here a 29-year-old woman with severe nonsyndromic mental retardation and a balanced reciprocal translocation between chromosomes X and 15 [46,XX,t(X;15)(q13.3;cen)]. Methylation studies showed a 100% skewed X-inactivation in patient-derived lymphocytes indicating that the normal chromosome X is retained inactive. Physical mapping of the breakpoints localised the Xq13.3 breakpoint to within 3.9 kb of the first exon of the ZDHHC15 gene encoding a zinc-finger and a DHHC domain containing product. Expression analysis revealed that different transcript variants of the gene are expressed in brain. ZDHHC15-specific RT-PCR analysis on lymphocytes from the patient revealed an absence of ZDHHC15 transcript variants, detected in control samples. We suggest that the absence of the ZDHHC15 transcripts in this patient contributes to her phenotype, and that the gene is a strong candidate for nonsyndromic XLMR.

Adult↗

PubMed2005

Interactions between RPS19, mutated in Diamond-Blackfan anemia, and the PIM-1 oncoprotein.

BACKGROUND AND OBJECTIVES: Diamond Blackfan anemia (DBA) is a congenital disease characterized by defective erythroid progenitor maturation. Patients' bone marrow progenitor cells do not respond to erythropoietic growth factors, such as erythropoietin. Mutations in the gene encoding for ribosomal protein (RP) S19 account for 25% of cases of DBA. The link between defective erythropoiesis and RPS19 is still unclear. Two not mutually exclusive hypotheses have been proposed: altered protein synthesis and loss of unknown extraribosomal functions. DESIGN AND METHODS: We used yeast two-hybrid screening and a human liver cDNA library obtained at 19-24 weeks of gestation, when hepatic erythropoiesis is efficient, to search for proteins interacting with RPS19. RESULTS: We found that RPS19 binds PIM-1, an ubiquitous serine-threonine kinase whose expression can be induced in erythropoietic cells by several growth factors, such as erythropoietin. The PIM-1/RPS19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of RPS19 in an in vitro kinase assay. We also showed that in human 293T cells PIM-1 interacts with ribosomes and may be involved in translational control. Three DBA-associated RPS19 mutations alter the binding between RPS19 and PIM-1. INTERPRETATION AND CONCLUSIONS: A link between erythropoietic growth factor signaling and RPS19 has been identified for the first time.

Amino Acid Sequence↗

PubMed2004

Deficiency of ribosomal protein S19 in CD34+ cells generated by siRNA blocks erythroid development and mimics defects seen in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia in which 25% of the patients have a mutation in the ribosomal protein S19 (RPS19) gene. To study effects of RPS19 deficiency in hematopoiesis we transduced CD34(+) umbilical cord blood (CB) and bone marrow (BM) cells with 3 lentiviral vectors expressing small interfering RNA (siRNA) against RPS19 and 1 scrambled control vector. All vectors also express green fluorescent protein (GFP). Transduction with the siRNA vectors reduced RPS19 mRNA levels to various degrees, which resulted in erythroid defects, correlating to the degree of RPS19 down-regulation, and was rescued by expression of an siRNA-resistant RPS19 transcript. Erythroid colony formation capacity conjointly decreased with RPS19 levels in CD34(+) CB and BM cells. In liquid culture supporting erythroid differentiation, RPS19-silenced as well as DBA patient CD34(+) cells exhibited reduced proliferative capacity and impaired erythroid differentiation resulting in fewer erythroid colony-forming units (CFU-Es). When assaying myeloid development, a less pronounced influence on proliferation was seen. This study shows for the first time that RPS19 silencing decreases the proliferative capacity of hematopoietic progenitors and leads to a defect in erythroid development.

Anemia, Diamond-Blackfan↗

PubMed2004

Targeted disruption of the ribosomal protein S19 gene is lethal prior to implantation.

The ribosomal protein S19 (RPS19) is located in the small (40S) subunit and is one of 79 ribosomal proteins. The gene encoding RPS19 is mutated in approximately 25% of patients with Diamond-Blackfan anemia, which is a rare congenital erythroblastopenia. Affected individuals present with decreased numbers or the absence of erythroid precursors in the bone marrow, and associated malformations of various organs are common. We produced C57BL/6J mice with a targeted disruption of murine Rps19 to study its role in erythropoiesis and development. Mice homozygous for the disrupted Rps19 were not identified as early as the blastocyst stage, indicating a lethal effect. In contrast, mice heterozygous for the disrupted Rps19 allele have normal growth and organ development, including that of the hematopoietic system. Our findings indicate that zygotes which are Rps19(-/-) do not form blastocysts, whereas one normal Rps19 allele in C57BL/6J mice is sufficient to maintain normal ribosomal and possibly extraribosomal functions.

Anemia, Diamond-Blackfan↗

PubMed2003

The role of hMLH3 in familial colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is commonly associated with at least three currently known DNA mismatch repair genes: (a) hMSH2; (b) hMLH1; and (c) hMSH6. A majority of HNPCC families has identifiable mutations in hMLH1 and hMSH2. When these mutations cause an inherited risk of colorectal cancer, they are also most often associated with microsatellite instability in the tumors. Recently, hMLH3 was suggested to be causative in HNPCC. We screened 70 index patients suggestive of a genetic predisposition for germ-line mutations in hMLH3 with denaturing high-performance liquid chromatography. One frameshift mutation and 11 missense mutations were identified in 16 index patients (23%). Most families presented evidence against hMLH3 as a high risk factor in familial colorectal cancer, and most of the mutations were found in the low risk patients, suggesting hMLH3 to be a low risk gene for colorectal cancer. We demonstrate in one family that a hMLH3 mutation segregated with disease together with a missense mutation in hMSH2, which makes us hypothesize that these mutations work together in an additive manner and result in an elevated risk of colorectal tumors in the family. None of the tumors with hMLH3 mutations showed microsatellite instability, which demonstrates that hMLH3 does not make its contribution to carcinogenesis through an impaired DNA mismatch repair function.

Carrier Proteins↗

PubMed2003

Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient diamond-Blackfan anemia improves following RPS19 gene transfer.

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.

Anemia, Diamond-Blackfan↗

PubMed2003

A candidate region for Asperger syndrome defined by two 17p breakpoints.

Asperger syndrome (AS) is a mild form of autistic disorder characterised by impairment in social interaction as well as a restricted pattern of behaviour, interests, and activities. Two patients with AS and balanced translocations t(13;17) and t(17;19), respectively, were identified. Fluorescent in situ hybridisation (FISH) analysis with chromosome 17 specific clones to metaphase chromosomes from both patients showed that the chromosome 17 breakpoints are located within a 300 kb region at 17p13. The region spans 14 known genes. The expression of these genes was analysed in lymphoblastoid RNA derived from the patients and healthy control individuals. The CHRNE, DKFZP566H073, LOC90048, PFN1, SPAG7, KIAA0909, ZNF232 and KIF1C genes showed similar levels of expression in cell lines with the translocations when compared with cell lines with normal karyotype. No expression was detected for the MINK, GP1BA, SLC25A11, ENO3, FLJ10060 and USP6 genes in any of the cell lines. The close physical relation of the two 17p breakpoints suggest a common genetic aetiology for the phenotype in the patients. Structural and functional analysis of the genes located around the two 17p breakpoints in t(13;17) and t(17;19) patients may reveal candidate sequences for the AS phenotype.

Adolescent↗

PubMed2003

Autosomal recessive congenital ichthyosis in Sweden and Estonia: clinical, genetic and ultrastructural findings in eighty-three patients.

Congenital (non-bullous) ichthyosis is a rare group of keratinizing disorders which can be tentatively subclassified based on clinical criteria, analysis of transglutaminase 1 gene mutations and electron microscopy of epidermis. We studied 83 patients who were all on topical therapy and in 16 cases also on oral retinoids. Three main groups of patients were distinguished: (A) those with transglutaminase 1 gene mutations (n=44), (B) those without transglutaminase 1 gene mutations showing a coarse, generalized scaling (n=19), and (C) those without transglutaminase 1 gene mutations showing only fine or focal scaling (n=20). On clinical scoring, patients in group A were more hyperkeratotic and less erythematous than those in group B (p < 0.05). Anhidrosis was recorded in nearly all patients (> or = 80%), but ectropion and a collodion phenotype at birth were more common in group A versus other groups. Ultrastructurally, a high frequency of type I (Anton-Lamprecht's classification) was found in all three groups (37-63%), 20 cases of type II in group A and a few cases of types III and IV in groups B and C, respectively. In conclusion, transglutaminase 1 gene mutation is a major cause of congenital ichthyosis in Sweden and Estonia, and is often associated with severe scaling and ultrastructural type II in corneocytes. The transglutaminase-unrelated cases are more heterogeneous, probably reflecting a more varied aetiology.

Adolescent↗

PubMed2003

Sustained cyclosporine-induced erythropoietic response in identical male twins with diamond-blackfan anemia.

After failing a trial of corticosteroid therapy, molecularly proven identical twins were treated for transfusion-dependent Diamond-Blackfan anemia with cyclosporine A, resulting in a robust erythropoietic response and a reversal of anemia. Clonogenic assays of marrow hematopoietic progenitors from both patients showed exuberant growth of BFU-E colonies but absent CFU-E. Clinically, the response has been sustained, and both patients have continued cyclosporine therapy and have been transfusion-independent for more than 27 months.

Anemia, Diamond-Blackfan↗