| 1. |
- Kariminejad, Ariana, et al.
(författare)
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Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia
- 2019
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 105:6, s. 1294-1301
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Tidskriftsartikel (refereegranskat)abstract
- The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.
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| 2. |
- Sedghi, Maryam, et al.
(författare)
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Motor neuron diseases caused by a novel VRK1 variant - A genotype/phenotype study
- 2019
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Ingår i: Annals of Clinical and Translational Neurology. - : John Wiley & Sons. - 2328-9503. ; 6:11, s. 2197-2204
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Tidskriftsartikel (refereegranskat)abstract
- Background Motor neuron disorders involving upper and lower neurons are a genetically and clinically heterogenous group of rare neuromuscular disorders with overlap among spinal muscular atrophies (SMAs) and amyotrophic lateral sclerosis (ALS). Classical SMA caused by recessive mutations in SMN1 is one of the most common genetic causes of mortality in infants. It is characterized by degeneration of anterior horn cells in the spinal cord, leading to progressive muscle weakness and atrophy. Non-SMN1-related spinal muscular atrophies are caused by variants in a number of genes, including VRK1, encoding the vaccinia-related kinase 1 (VRK1). VRK1 variants have been segregated with motor neuron diseases including SMA phenotypes or hereditary complex motor and sensory axonal neuropathy (HMSN), with or without pontocerebellar hypoplasia or microcephaly. Results Here, we report an association of a novel homozygous splice variant in VRK1 (c.1159 + 1G>A) with childhood-onset SMA or juvenile lower motor disease with brisk tendon reflexes without pontocerebellar hypoplasia and normal intellectual ability in a family with five affected individuals. We show that the VRK1 splice variant in patients causes decreased splicing efficiency and a mRNA frameshift that escapes the nonsense-mediated decay machinery and results in a premature termination codon. Conclusions Our findings unveil the impact of the variant on the VRK1 transcript and further support the implication of VRK1 in the pathogenesis of lower motor neuron diseases.
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| 3. |
- Abusibaa, W. A., et al.
(författare)
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Expression of the GBGT1 Gene and the Forssman Antigen in Red Blood Cells in a Palestinian Population
- 2019
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Ingår i: Transfusion Medicine and Hemotherapy. - : S. Karger AG. - 1660-3796 .- 1660-3818. ; 46:6, s. 450-454
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Forssman antigen (FORS1 Ag) is expressed on human red blood cells (RBCs). We investigated its presence on RBCs from Palestinian subjects and Swedish subjects by serological testing and by sequencing part of exon 7 of the GBGT1 gene, which encodes Forssman synthase. -Materials and Methods: Blood samples from Palestinian subjects (n = 211 adults and n = 73 newborns) and from Swedish subjects (n = 47 adults) were analyzed in the study. RBCs from the Palestinian samples were typed for the FORS1 Ag using a monoclonal anti-Forssman antibody. The GBGT1 gene was genotyped by DNA sequencing (all adult samples) or by using amplification refractory mutation system PCR (newborn samples). Results: All of the studied samples were negative for the FORS1 Ag by serologic typing. DNA sequencing of the 3′ end of exon 7 of the GBGT1 gene, which includes Arg296, showed that all samples had the wild-type Arg296 sequence, which is associated with an inactive form of Forssman synthase. We detected four single nucleotide polymorphisms in the adult samples; two were silent (p.Tyr232=, p.Gly290=), and two were missense (p.Arg243Cys, p.Arg243His). The allele frequencies ranged from 0.2 to 3.6%. The p.Arg243Cys SNP was a novel SNP that was detected in one Palestinian sample. Conclusion: Our results confirmed the allelic diversity of GBGT1 and identified a novel nucleotide polymorphism in this gene, p.Arg243Cys. Our results also confirmed that the FORS blood group system is a low-frequency system. © 2019 S. Karger AG, Basel. Copyright: All rights reserved.
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| 4. |
- Björkman, Kristoffer, et al.
(författare)
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Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1.
- 2015
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Ingår i: Mitochondrion. - : Elsevier BV. - 1872-8278 .- 1567-7249. ; 21, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- We report clinical, metabolic, genetic and neuroradiological findings in five patients from three different families with isolated complex I deficiency. Genetic analysis revealed mutations in NDUFS1 in three patients and in NDUFV1 in two patients. Four of the mutations are novel and affect amino acid residues that either are invariant among species or conserved in their properties. The presented clinical courses are characterized by leukoencephalopathy or early death and expand the already heterogeneous phenotypic spectrum. A literature review was performed, showing that patients with mutations in NDUFS1 in general have a worse prognosis than patients with mutations in NDUFV1.
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| 5. |
- Darin, Niklas, 1964, et al.
(författare)
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Benign mitochondrial myopathy with exercise intolerance in a large multigeneration family due to a homoplasmic m.3250T>C mutation in MTTL1.
- 2017
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Ingår i: European journal of neurology. - : Wiley. - 1468-1331 .- 1351-5101. ; 24:4, s. 587-593
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Tidskriftsartikel (refereegranskat)abstract
- Most mitochondrial disorders with onset in early childhood are progressive and involve multiple organs. The m.3250T>C mutation in MTTL1 has previously been described in a few individuals with a possibly riboflavin-responsive myopathy and an association with sudden infant death syndrome was suspected. We describe a large family with this mutation and evaluate the effect of riboflavin treatment.Medical data were collected with the help of a standardized data collection form. Sanger sequencing was used to screen for variants in mitochondrial DNA and the proportion of the mutation was analyzed in different tissues. Biochemical and muscle morphological investigations of muscle tissue were performed in two individuals. The effect of riboflavin treatment was evaluated in two individuals.Thirteen family members experienced exercise intolerance with fatigue and weakness. Inheritance was maternal with 100% penetrance. The course was either static or showed improvement over time. There was no evidence of other organ involvement except for a possible mild transient cardiac enlargement in one child. Muscle investigations showed isolated complex I deficiency and mitochondrial proliferation. The level of m.3250T>C was apparently 100%, i.e. homoplasmic, in all examined tissues. Riboflavin treatment showed no effect in any treated family member and there have been no cases of sudden infant death in this family.This study illustrates the importance of considering mitochondrial disorders in the work-up of individuals with exercise intolerance and provides a better understanding of the phenotype associated with the m.3250T>C mutation in MTTL1.
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| 6. |
- Jesus, C., et al.
(författare)
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Prevalence of antibodies to a new histo-blood system: the FORS system
- 2018
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Ingår i: Blood Transfusion. - 1723-2007. ; 16:2, s. 178-183
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Tidskriftsartikel (refereegranskat)abstract
- Background. In 1987, three unrelated English families were reported with a putative blood subgroup called A pae. Swedish researchers later found evidence leading to abolishment of the A pae subgroup and establishment instead of the FORS blood group system (System 31 -ISBT, 2012). It is important to know the prevalence of antibodies in order to make the best decisions in transfusion medicine. Cells expressing the Forssman saccharide, such as sheep erythrocytes, are needed to detect the anti-Forssman antibody. The aim of this study was to define the prevalence of human anti-Forssman antibody. Materials and methods. Plasma samples from 800 individuals were studied. Sheep erythrocytes or Forssman "kodecytes" were mixed with the plasma samples using the tube technique. Plasma from an A pae individual was used as a negative control and monoclonal anti-Forssman antibody (M1/22.25.8HL cell line supernatant) was used as the positive control. Results. Of the 800 individuals tested, one was negative for the presence of anti-Forssman antibody. We compared the anti-Forssman antibody reaction pattern between genders and found that males have weaker reactions than females, both at room temperature (p= 0.026) and at 37 degrees C (p= 0.043). We also investigated the reaction pattern of anti-Forssman antibody in relation to ABO and Rh blood group types without finding any significant differences. Discussion. Sheep erythrocytes are suitable for searching for human anti-Forssman antibody. The quantity of anti-Forssman antibodies in plasma is higher in females than in males. In the population (n= 800) studied here, we found one individual lacking the anti-Forssman antibody. These results contribute to the data already published, confirming that FORS is a rare blood group.
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| 7. |
- Kariminejad, A., et al.
(författare)
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Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum
- 2016
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Ingår i: Bmc Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lethal multiple pterygium syndrome (LMPS, OMIM 253290), is a fatal disorder associated with anomalies of the skin, muscles and skeleton. It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis. Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS. This study aimed to uncover the aetiology of LMPS in a family with two affected foetuses. Methods and results: Whole exome sequencing studies have identified novel compound heterozygous mutations in RYR1 in two affected foetuses with pterygium, severe arthrogryposis and foetal hydrops with cystic hygroma, characteristic features compatible with LMPS. The result was confirmed by Sanger sequencing and restriction fragment length polymorphism analysis. Conclusions: RYR1 encodes the skeletal muscle isoform ryanodine receptor 1, an intracellular calcium channel with a central role in muscle contraction. Mutations in RYR1 have been associated with congenital myopathies, which form a continuous spectrum of pathological features including a severe variant with onset in utero with fetal akinesia and arthrogryposis. Here, the results indicate that LMPS can be considered as the extreme end of the RYR1-related neonatal myopathy spectrum. This further supports the concept that LMPS is a severe disorder associated with defects in the process known as excitation-contraction coupling.
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| 8. |
- Kariminejad, A., et al.
(författare)
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Truncating CHRNG mutations associated with interfamilial variability of the severity of the Escobar variant of multiple pterygium syndrome
- 2016
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Ingår i: Bmc Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: In humans, muscle-specific nicotinergic acetylcholine receptor (AChR) is a transmembrane protein with five different subunits, coded by CHRNA1, CHRNB, CHRND and CHRNG/CHRNE. The gamma subunit of AChR encoded by CHRNG is expressed during early foetal development, whereas in the adult, the. subunit is replaced by a epsilon subunit. Mutations in the CHRNG encoding the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome. The MPS is a condition characterised by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis. Results: Our whole exome sequencing studies have identified one novel and two previously reported homozygous mutations in CHRNG in three families affected by non-lethal EVMPS. The mutations consist of deletion of two nucleotides, cause a frameshift predicted to result in premature termination of the foetally expressed gamma subunit of the AChR. Conclusions: Our data suggest that severity of the phenotype varies significantly both within and between families with MPS and that there is no apparent correlation between mutation position and clinical phenotype. Although individuals with CHRNG mutations can survive, there is an increased frequency of abortions and stillbirth in their families. Furthermore, genetic background and environmental modifiers might be of significance for decisiveness of the lethal spectrum, rather than the state of the mutation per se. Detailed clinical examination of our patients further indicates the changing phenotype from infancy to childhood.
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| 9. |
- Lindgren, Ulrika, et al.
(författare)
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Mitochondrial pathology in inclusion body myositis
- 2015
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 25:4, s. 281-288
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Tidskriftsartikel (refereegranskat)abstract
- Inclusion body myositis (IBM) is usually associated with a large number of cytochrome c oxidase (COX)-deficient muscle fibers and acquired mitochondrial DNA (mtDNA) deletions. We studied the number of COX-deficient fibers and the amount of mtDNA deletions, and if variants in nuclear genes involved in mtDNA maintenance may contribute to the occurrence of mtDNA deletions in IBM muscle. Twenty-six IBM patients were included. COX-deficient fibers were assayed by morphometry and mtDNA deletions by qPCR. POLG was analyzed in all patients by Sanger sequencing and C10orf2 (Twinkle), DNA2, MGME1, OPA1, POLG2, RRM2B, SLC25A4 and TYMP in six patients by next generation sequencing. Patients with many COX-deficient muscle fibers had a significantly higher proportion of mtDNA deletions than patients with few COX-deficient fibers. We found previously unreported variants in POLG and C10orf2 and IBM patients had a significantly higher frequency of an RRM2B variant than controls. POLG variants appeared more common in IBM patients with many COX-deficient fibers, but the difference was not statistically significant. We conclude that COX-deficient fibers in inclusion body myositis are associated with multiple mtDNA deletions. In IBM patients we found novel and also previously reported variants in genes of importance for mtDNA maintenance that warrants further studies. (C) 2014 Elsevier B.V. All rights reserved.
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| 10. |
- Pokrzywa, Malgorzata, 1977, et al.
(författare)
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Developmental MYH3 Myopathy Associated with Expression of Mutant Protein and Reduced Expression Levels of Embryonic MyHC
- 2015
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Ingår i: PLoS One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Objective An essential role for embryonic MyHC in foetal development has been found from its association with distal arthrogryposis syndromes, a heterogeneous group of disorders characterised by congenital contractions. The latter probably result from severe myopathy during foetal development. Lack of embryonic muscle biopsy material and suitable animal models has hindered study of the pathomechanisms linking mutations in MYH3 to prenatal myopathy. We determined the pathomechanisms of developmental myopathy caused by recurrent p. Thr178Ile MYH3 heterozygosity, using patient-derived skeletal muscle cells in culture as an experimental disease model to emulate early embryonic development. These cultured cells were processed for discrimination and quantitative analysis of mutant and wild-type MYH3 alleles and MyHC transcripts, real-time RT-qPCR, sequence analysis, immunofluorescence microscopy, immunoblot, and proteomic assessments. Involvement of the ubiquitin proteasome system was investigated in patients with p. Thr178Ile mutations in MYH3 and MYH2. We found equal overall expression of mutant and wild-type MyHC mRNAs and proteins. Compared to the controls, however, expression of embryonic MyHC transcripts and proteins was reduced whereas expression of myosin-specific E3 ubiquitin ligase (MuRF1) was increased. We also found delayed myofibrillogenesis and atrophic myotubes but structured sarcomeres. In conclusion, this study suggests that developmental p.Thr178Ile MYH3 myopathy is associated with a combined pathomechanism of insufficient dosage of functional embryonic MyHC and production of mutant protein.
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