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| 2. |
- Pagnamenta, A. T., et al.
(författare)
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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 584-600
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose 47000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 +/- 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.
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| 3. |
- Hammarsjo, A, et al.
(författare)
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Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 15585-
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Tidskriftsartikel (refereegranskat)abstract
- The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.
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| 4. |
- Mitrovic, I. Z., et al.
(författare)
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Atomic-layer deposited thulium oxide as a passivation layer on germanium
- 2015
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 117:21
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive study of atomic-layer deposited thulium oxide (Tm2O3) on germanium has been conducted using x-ray photoelectron spectroscopy (XPS), vacuum ultra-violet variable angle spectroscopic ellipsometry, high-resolution transmission electron microscopy (HRTEM), and electron energy-loss spectroscopy. The valence band offset is found to be 3.05±0.2eV for Tm2O3/p-Ge from the Tm 4d centroid and Ge 3p3/2 charge-corrected XPS core-level spectra taken at different sputtering times of a single bulk thulium oxide sample. A negligible downward band bending of ∼0.12eV is observed during progressive differential charging of Tm 4d peaks. The optical band gap is estimated from the absorption edge and found to be 5.77eV with an apparent Urbach tail signifying band gap tailing at ∼5.3eV. The latter has been correlated to HRTEM and electron diffraction results corroborating the polycrystalline nature of the Tm2O3 films. The Tm2O3/Ge interface is found to be rather atomically abrupt with sub-nanometer thickness. In addition, the band line-up of reference GeO2/n-Ge stacks obtained by thermal oxidation has been discussed and derived. The observed low reactivity of thulium oxide on germanium as well as the high effective barriers for holes (∼3eV) and electrons (∼2eV) identify Tm2O3 as a strong contender for interfacial layer engineering in future generations of scaled high-κ gate stacks on Ge.
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| 5. |
- Mitrovic, I. Z., et al.
(författare)
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Interface engineering routes for a future cmos ge-based technology
- 2014
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Ingår i: ECS Transactions. - : The Electrochemical Society. - 1938-5862 .- 1938-6737. ; , s. 73-88
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Konferensbidrag (refereegranskat)abstract
- We present an overview study of two germanium interface engineering routes, firstly a germanate formation via La2O3 and Y2O3, and secondly a barrier layer approach using Al2O3 and Tm2O3. The interfacial composition, uniformity, thickness, band gap, crystallinity, absorption features and valence band offset are determined using X-ray photoelectron spectroscopy, ultra violet variable angle spectroscopic ellipsometry, and high resolution transmission electron microscopy. The correlation of these results with electrical characterization data make a case for Ge interface engineering with rare-earth inclusion as a viable route to achieve high performance Ge CMOS.
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| 6. |
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| 7. |
- Mitrovic, I. Z., et al.
(författare)
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Interface engineering of Ge using thulium oxide : Band line-up study
- 2013
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Ingår i: Microelectronic Engineering. - : Elsevier. - 0167-9317 .- 1873-5568. ; 109, s. 204-207
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Tidskriftsartikel (refereegranskat)abstract
- This paper investigates the band line-up and optical properties (dielectric function) of Tm2O3/Ge gate stacks deposited by atomic layer deposition. X-ray photoelectron spectroscopy has been performed to ascertain the shallow core levels (Ge3d and Tm4d) in ultra-thin and bulk Tm2O3/Ge stacks as well as valence band maxima in Ge and bulk Tm2O3. The valence band offset of Tm2O3/Ge has been found to be 2.95 +/- 0.08 eV. Vacuum ultra violet variable angle spectroscopic ellipsometry studies reveal the indirect band gap nature of Tm2O3, with the value extracted from the Tauc method of 5.3 +/- 0.1 eV. A distinct absorption feature is observed at similar to 3.2 eV below the band gap of Tm2O3, and clearly distinguished from the Si and Ge critical points. A dielectric constant of 14 to 15 has been derived from the electrical measurements on 5 nm Tm2O3/epi Ge/Si gate stacks. The band line-up study of Tm2O3/Ge implies an acceptable barrier for holes (2.95 eV) and electrons (greater than 1.7 eV) for Ge MOSFET engineering.
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| 8. |
- Sedghi, M., et al.
(författare)
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Ataxia-telangiectasia-like disorder in a family deficient for MRE11A, caused by a MRE11 variant
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We report 3 siblings with the characteristic features of ataxia-telangiectasia-like disorder associated with a homozygous MREll synonymous variant causing nonsense-mediated mRNA decay (NMD) and MRE11A deficiency. Clinical assessments, next-generation sequencing, transcript and immunohistochemistry analyses were performed. The patients presented with poor balance, developmental delay during the first year of age, and suffered from intellectual disability from early childhood. They showed oculomotor apraxia, slurred and explosive speech, limb and gait ataxia, exaggerated deep tendon reflex, dystonic posture, and mirror movement in their hands. They developed mild cognitive abilities. Brain MRI in the index case revealed cerebellar atrophy. Next-generation sequencing revealed a homozygous synonymous variant in MRE11 (c.657C>T, p.Asn219=) that we show affects splicing. A complete absence of MREll transcripts in the index case suggested NMD and immunohistochemistry confirmed the absence of a stable protein. Despite the critical role of MRE11A in double-strand break repair and its contribution to the Mre11/Rad50/Nbs1 complex, the absence of MRE11A is compatible with life.
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| 9. |
- Sedghi, M., et al.
(författare)
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Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP
- 2019
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases, and with a complex phenotype with immunodeficiency, skin changes and myelodysplasia. MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication. In this study, we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause. The affected individuals were homozygous for a missense MCM3AP variant, located at the Sac3 domain, which was predicted to affect conserved amino acid likely important for the function of the germinal-centre associated nuclear protein. Our data support further expansion of the clinical spectrum linked to MCM3AP variant and highlight that MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis.
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