Bjørn Ivar Haukanes - Academia.edu (original) (raw)

Papers by Bjørn Ivar Haukanes

European journal of human genetics, May 22, 2024

European journal of biochemistry, Jun 1, 1992

ABSTRACT A redoxyendonuclease from calf thymus was purified to apparent homogeneity. The redoxyen... more ABSTRACT A redoxyendonuclease from calf thymus was purified to apparent homogeneity. The redoxyendonuclease recognized and induced cleavage of DNA damaged by ultraviolet light. The enzyme preparation produced a single band of a relative molecular mass of approximately 34 kDa upon SDS/PAGE. The apurinic/apyrimidinic endonuclease and the DNA glycosylase activities remained associated in the apparently homogeneous preparation of the enzyme. The redoxyendonuclease activity displayed a broad pH optimum between pH 5.0-8.5 and exhibited no requirement for divalent cations. By application of FPLC columns Mono-S, Mono-Q and Mono-P, the isoelectric point (pI) of the enzyme was found to be approximately 8.0. Using the DNA sequencing procedure of Maxam and Gilbert [Maxam, A. M. & Gilbert, W. (1980) Methods Enzymol. 65, 499-560] the purified enzyme was found to incise ultraviolet-light-irradiated DNA at pyrimidine sites as observed previously with a more crude form of the enzyme. While the most frequently cleavaged sites for the crude preparation were at cytosine residues, the apparently homogeneous enzyme preparation frequently induced cleavage sites at both cytosine and guanine residues. Predominant incision induced by the apparently homogeneous preparation was observed at guanine residues when a particular DNA sequence was used as substrate. Furthermore, the 16 N-terminal amino acid residues of the purified enzyme were identified. The sequence did not show any significant similarity to other known proteins.

Diabetes Research and Clinical Practice, Nov 1, 2017

Heterozygous mutations in hepatocyte nuclear factor-1A (HNF1A) cause maturity-onset diabetes of t... more Heterozygous mutations in hepatocyte nuclear factor-1A (HNF1A) cause maturity-onset diabetes of the young type 3 (MODY3). Our aim was to compare two families with suspected dominantly inherited diabetes and a new HNF1A variant of unknown clinical significance. Methods The HNF1A gene was sequenced in two independently recruited families from the Norwegian MODY Registry. Both familes were phenotyped clinically and biochemically. Microsatellite markers around and within the HNF1A locus were used for haplotyping. Chromosomal linkage analysis was performed in one family, and whole-exome sequencing was undertaken in two affected family members from each family. Transactivation activity, DNA binding and nuclear localization of wild type and mutant HNF-1A were assessed. Results The novel HNF1A variant c.539C>T (p.Ala180Val) was found in both families. The variant fully co-segregated with diabetes in one family. In the other family, two subjects with diabetes mellitus and one with normal glucose levels were homozygous variant carriers. Chromosomal linkage of diabetes to the HNF1A locus or to other genomic regions could not be established. The protein functional studies did not reveal significant differences between wild type and variant HNF-1A. In each family, whole-exome sequencing failed to identify any other variant that could explain the disease. Conclusions The HNF1A variant p.Ala180Val does not seem to cause MODY3, although it may confer risk for type 2 diabetes mellitus. Our data demonstrate challenges in causality evaluation of rare variants detected in known diabetes genes.

Familial Cancer, Jan 4, 2022

Pathogenic germline variants in Breast cancer susceptibility gene 1 (BRCA1) predispose carriers t... more Pathogenic germline variants in Breast cancer susceptibility gene 1 (BRCA1) predispose carriers to hereditary breast and ovarian cancer (HBOC). Through genetic testing of patients with suspected HBOC an increasing number of novel BRCA1 variants are discovered. This creates a growing need to determine the clinical significance of these variants through correct classification (class 1-5) according to established guidelines. Here we present a joint collection of all BRCA1 variants of class 2-5 detected in the four diagnostic genetic laboratories in Norway. The overall objective of the study was to generate an overview of all BRCA1 variants in Norway and unveil potential discrepancies in variant interpretation between the hospitals, serving as a quality control at the national level. For a subset of variants, we also assessed the change in classification over a ten-year period with increasing information available. In total, 463 unique BRCA1 variants were detected. Of the 126 variants found in more than one hospital, 70% were interpreted identically, while 30% were not. The differences in interpretation were mainly by one class (class 2/3 or 4/5), except for one larger discrepancy (class 3/5) which could affect the clinical management of patients. After a series of digital meetings between the participating laboratories to disclose the cause of disagreement for all conflicting variants, the discrepancy rate was reduced to 10%. This illustrates that variant interpretation needs to be updated regularly, and that data sharing and improved national inter-laboratory collaboration greatly improves the variant classification and hence increases the accuracy of cancer risk assessment.

Molecular Case Studies, 2021

Here we describe for the first time double paternal uniparental isodisomy (iUPD) 7 and 15 in a ba... more Here we describe for the first time double paternal uniparental isodisomy (iUPD) 7 and 15 in a baby boy with features in the Beckwith–Wiedemann syndrome spectrum (BWSp) (placentomegaly, hyperinsulinism, enlarged viscera, hemangiomas, and earlobe creases) in addition to conjugated hyperbilirubinemia. His phenotype was also reminiscent of genome-wide paternal uniparental isodisomy. We discuss the most likely origin of the UPDs: a maternal double monosomy 7 and 15 rescued by duplication of the paternal chromosomes after fertilization. So far, paternal UPD7 is not associated with an abnormal phenotype, whereas paternal UPD15 causes Angelman syndrome. Methylation analysis for other clinically relevant imprinting disorders, including BWSp, was normal. Therefore, we hypothesized that the double UPD affected other imprinted genes. To look for such effects, patient fibroblast RNA was isolated and analyzed for differential expression compared to six controls. We did not find apparent transcri...

Antiviral Research, 1995

... However, unlike PFA - resistant HIV - 1, which is hypersusceptible to Nevirapine, TIBO R82150... more ... However, unlike PFA - resistant HIV - 1, which is hypersusceptible to Nevirapine, TIBO R82150 and AZT, RT 161208 was as susceptible to Nevirapine and TIBO R82150 as wt RT. ... Language:English. Document Type: Abstract. DOI: 10.1016/0166-3542(95)94777-Y. ...

Genes, Jan 19, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

BMC Cancer

Background Damaging alterations in the BRCA1 gene have been extensively described as one of the m... more Background Damaging alterations in the BRCA1 gene have been extensively described as one of the main causes of hereditary breast and ovarian cancer (HBOC). BRCA1 alterations can lead to impaired homologous recombination repair (HRR) of double-stranded DNA breaks, a process which involves the RING, BRCT and coiled-coil domains of the BRCA1 protein. In addition, the BRCA1 protein is involved in transcriptional activation (TA) of several genes through its C-terminal BRCT domain. Methods In this study, we have investigated the effect on HRR and TA of 11 rare BRCA1 missense variants classified as variants of uncertain clinical significance (VUS), located within or in close proximity to the BRCT domain, with the aim of generating additional knowledge to guide the correct classification of these variants. The variants were selected from our previous study “BRCA1 Norway”, which is a collection of all BRCA1 variants detected at the four medical genetic departments in Norway. Results All vari...

European Journal of Human Genetics, 2018

Autism Research, 2022

LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific con... more LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%-26% lower than expected from Hardy-Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. Lay Summary LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher-functioning autism is more common in males than females.

Genetics in Medicine, 2021

Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function... more Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Molecular Syndromology, 2018

A 4-generation family with multiple synostoses syndrome type 4 (SYNS4) is reported, the third fam... more A 4-generation family with multiple synostoses syndrome type 4 (SYNS4) is reported, the third family identified so far. The phenotype segregated with a previously undescribed Asn399Lys (c.1197C>A) substitution in GDF6. N399 is part of a hydrophobic pocket critical for binding the BMP/GDF antagonist noggin. The N399K substitution renders GDF6 more similar to noggin-resistant members of the BMP family, namely GDF2 and BMP10, both of which contain lysine in the corresponding position. To further define the SYNS4 phenotype, we examined 6 of 9 affected family members. The phenotype was carpal and tarsal synostoses with painful feet after walking, but the condition could also be asymptomatic. Interestingly, unlike the previous SYNS4 families, the family presented here has no history of hearing loss, and a 73-year-old mutation carrier had normal audiometry for his age. Based on structure modelling, BMPR2 binding should not be affected by the GDF6-N399K substitution, unlike the S429R and...

PloS one, 2013

We employed whole exome sequencing to investigate three Norwegian siblings with an autosomal rece... more We employed whole exome sequencing to investigate three Norwegian siblings with an autosomal recessive spastic ataxia and epilepsy. All patients were compound heterozygous (c.13352T>C, p.Leu4451Pro; c.6890T>G, p.Leu2297Trp) for mutations in the SACS gene establishing the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The clinical features shown by our patients were typical of this disorder with the exception of epilepsy, which is a rare manifestation. This is the first report of ARSACS in Scandinavian patients and our findings expand the genetic and clinical spectrum of this rare disorder. Moreover, we show that exome sequencing is a powerful and cost-effective tool for the diagnosis of genetically heterogeneous disorders such as the hereditary ataxias.

Orphanet Journal of Rare Diseases, 2013

Background Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we ... more Background Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor. Methods We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions. Results A recessive genetic defect was suspected in two siblings of healthy, but consanguineous parents. Homozygosity mapping revealed three shared homozygous regions and exome sequencing, revealed a novel homozygous c.367 G>A [p.Asp123Asn] mutation in the α-methylacyl-coA racemase (AMACR) gene in both patients. The genetic diagnosis of α-methylacyl-coA racemase deficiency was c...

Orphanet Journal of Rare Diseases, 2014

Background: A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits ... more Background: A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism. Methods and results: With a combination of homozygozity mapping and exome sequencing, we identified three mutations in STUB1 in two families with ARCA and cognitive impairment; a homozygous missense variant (c.194A > G, p.Asn65Ser) that segregated in three affected siblings, and a missense change (c.82G > A, p.Glu28Lys) which was inherited in trans with a nonsense mutation (c.430A > T, p.Lys144Ter) in another patient. STUB1 encodes CHIP (C-terminus of Heat shock protein 70-Interacting Protein), a dual function protein with a role in ubiquitination as a co-chaperone with heat shock proteins, and as an E3 ligase. We show that the p.Asn65Ser substitution impairs CHIP's ability to ubiquitinate HSC70 in vitro, despite being able to self-ubiquitinate. These results are consistent with previous studies highlighting this as a critical residue for the interaction between CHIP and its co-chaperones. Furthermore, we show that the levels of CHIP are strongly reduced in vivo in patients' fibroblasts compared to controls. Conclusions: These results suggest that STUB1 mutations might cause disease by impacting not only the E3 ligase function, but also its protein interaction properties and protein amount. Whether the clinical heterogeneity seen in STUB1 ARCA can be related to the location of the mutations remains to be understood, but interestingly, all siblings with the p.Asn65Ser substitution showed a marked appearance of accelerated aging not previously described in STUB1 related ARCA, none display hormonal aberrations/clinical hypogonadism while some affected family members had diabetes, alopecia, uveitis and ulcerative colitis, further refining the spectrum of STUB1 related disease.

Neuromuscular Disorders, 2010

Journal of Medical Genetics, 2010

Cancer Immunology, Immunotherapy, 2009

Patients with cancer may develop paraneoplastic neurological syndromes (PNS) in which onconeural ... more Patients with cancer may develop paraneoplastic neurological syndromes (PNS) in which onconeural antibodies are important diagnostic findings. As the functional role of onconeural antibodies is largely unknown, insight gained by identifying associated antibodies may help to clarify the pathogenesis of the PNS. In this study, we identified patients with Yo antibodies who also had antibodies to an uncharacterized protein called coiled-coil domain-containing protein 104 (CCDC104). We found a significant association between CCDC104 and Yo antibodies (4 of 38, 10.5%), but not other onconeural antibodies (0 of 158) (P = 0.007, Fisher's exact test). The prevalence of CCDC104 antibodies was approximately similar in patients with cancer (8 of 756, 1.1%) and in healthy blood donors (2 of 300, 0.7%). CCDC104 antibodies were not associated with PNS, as this was found in only two of the ten CCDC104-positive patients. The CCDC104 protein, whose function is unknown, is expressed in various human tissues, including the brain, and is localized mainly to the nucleus, but is also found in the cytoplasm. The association between Yo and CCDC104 antibodies may indicate functional similarities.

American Journal of Medical Genetics Part A, 2007

The prevalence of duplications and deletions of the 22q11.2 (DiGeorge syndrome) region was studie... more The prevalence of duplications and deletions of the 22q11.2 (DiGeorge syndrome) region was studied among babies born in Norway with open cleft palate without cleft lip (cleft palate only, CPO). During a 5-year period (1996-2001), there were 245 live births with CPO that were referred for surgery. DNA was available from 174 cases with overt cleft palate. DNA copy number was analyzed with the multiplex ligation-dependent probe amplification (MLPA) technique, and an unambiguous result was obtained in 169 (97%) of the samples. We found no 22q11.2 duplications, and one known, and two previously undiagnosed cases with 22q11.2 deletions. All three del22q11-syndrome cases also had heart malformations, which represent one-third of the 10 babies with heart malformations in our study population. The prevalence of del22q11-syndrome among babies with cleft palate with or without additional malformations was 1 of 57 (1.8%). Because the prevalence of CPO in the 35 22q11.2 duplication cases published was 20%, we also investigated if dup22q11-testing was warranted in this group. However, no 22q11.2 duplications were found, indicating that the duplication cases ascertained so far might not be representative of the dup22q11-group as a whole. We conclude that neither del22q11 nor dup22q11 testing is warranted in babies with overt cleft palate as the only finding.