| 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. |
- Abdul-Hussein, Saba, et al.
(författare)
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Phenotypes of Myopathy-Related Beta-Tropomyosin Mutants in Human and Mouse Tissue Cultures
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:9
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of beta-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-beta-TMEGFP mutant showed perinuclear aggregates. The G53ins-beta-TMEGFP mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-beta-TMEGFP and E122K-beta-TMEGFP mutants induced the formation of rod-like structures in human cells. The N202K-beta-TMEGFP mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant beta-TMEGFP in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related beta-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein.
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| 4. |
- 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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| 5. |
- Andersson Grönlund, Marita, 1959-, et al.
(författare)
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Ophthalmological findings in children and young adults with genetically verified mitochondrial disease
- 2010
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Ingår i: British Journal of Ophthalmology. - : BMJ Publishing Group Ltd. - 0007-1161 .- 1468-2079. ; 94:1, s. 121-127
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To describe ophthalmological phenotypes in patients with mitochondrial disease and known genotypes.METHODS: A retrospective study was performed on 59 patients (29 male, 30 female) with a mean age of 11.8 years who had mitochondrial disease with known DNA mutations. Fifty-seven of the 59 subjects underwent a detailed ophthalmological examination including visual acuity (VA), eye motility, refraction, slit-lamp examination, ophthalmoscopy and, in almost one-half of the cases, a full-field electroretinogram (ERG).RESULTS: Forty-six (81%) of the patients had one or more ophthalmological findings such as ptosis (n = 16), reduced eye motility (n = 22) including severe external ophthalmoplegia (n = 9), strabismus (n = 4), nystagmus (n = 9), low VA (n = 21), refractive errors (n = 26), photophobia (n = 4), and partial or total optic atrophy (n = 25). Pigmentation in the macula and/or periphery was noted in 16 patients. In 10/27 investigated individuals with full field ERG, retinal dystrophy was recorded in six different genotypes representing Kearns-Sayre syndrome (n = 5), Leigh syndrome (n = 1), Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (n = 1), Myoclonus epilepsy with red ragged fibres (MERRF) (n = 1), Leber hereditary optic neuropathy (n = 1) and mitochondrial myopathy (n = 1).CONCLUSION: The results show that a majority of patients with mitochondrial disorders have ophthalmological abnormalities. We recommend that an ophthalmological examination, including ERG, be performed on all children and adolescents who are suspected of having a mitochondrial disease.
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| 6. |
- 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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| 7. |
- Björkman, Kristoffer, et al.
(författare)
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Genotype-phenotype correlations in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1
- 2014
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Ingår i: Euromit 2014, 15-19 juni, Tampere, Finland.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: To study genotype-phenotype correlations in genes encoding complex I electron input module subunits. Materials and methods: We studied five patients with isolated complex I deficiency, three with NDUFS1 mutations and two with NDUFV1 mutations. A literature review of all reported cases of mutations in the affected genes was performed. Results: The literature review revealed pathological mutations in NDUFS1 for 18 patients in 17 families and correspondingly in NDUFV1 for 26 patients in 19 families. Unpublished clinical data for our five patients were added. Our study showed quite variable clinical courses; death before two years of age was seen in 41% of patients while 18% were alive at seven years. There was a significant difference between the NDUFS1 and NDUFV1 groups for clinical onset and life-span. Mutations in NDUFS1 were linked to a worse clinical course with earlier onset and earlier death. Conclusions: Genotype-phenotype correlations in patients with mutations affecting the genes that encode the electron input module of complex I vary, but patients with NDUFS1 mutation tend to have a worse clinical course than patients with NDUFV1 mutation. Identifying the mutations is of importance for accurate prognostic information and genetic counseling.
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| 8. |
- Chatron, N., et al.
(författare)
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Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:5, s. 1447-1461
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Tidskriftsartikel (refereegranskat)abstract
- Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1(-/-) mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the c-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.
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| 9. |
- 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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| 10. |
- Darin, Niklas, 1964, et al.
(författare)
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Functional analysis of a novel POL gamma A mutation associated with a severe perinatal mitochondrial encephalomyopathy
- 2021
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 31:4, s. 348-358
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POL. A) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POL gamma A often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POL gamma A mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death. Muscle biopsy identified scattered COX-deficient muscle fibers, respiratory chain dysfunction and mtDNA depletion. We identified a novel POL.A mutation (p.His1134Tyr) in trans with the previously identified p.Thr251Ile/Pro587Leu double mutant. Biochemical characterization of the purified recombinant POL gamma A variants showed that the p.His1134Tyr mutation caused severe polymerase dysfunction. The p.Thr251Ile/Pro587Leu mutation caused reduced polymerase function in conditions of low dNTP concentration that mimic postmitotic tissues. Critically, when p.His1134Tyr and p.Thr251Ile/Pro587Leu were combined under these conditions, mtDNA replication was severely diminished and featured prominent stalling. Our data provide a molecular explanation for the patients mtDNA depletion and clinical features, particularly in tissues such as brain and muscle that have low dNTP concentration. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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| 11. |
- Darin, Niklas, 1964, et al.
(författare)
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Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I
- 2007
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Ingår i: Eur J Paediatr Neurol. - : Elsevier BV. ; 11:6, s. 353-7
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Tidskriftsartikel (refereegranskat)abstract
- Limb-girdle muscular dystrophy (LGMD) type 2I, caused by mutations in the fukutin-related protein gene (FKRP), is one of the most common forms of LGMD in childhood. We describe two patients with LGMD2I and a Duchenne-like phenotype. In addition to the common L276I mutation, both patients had a new mutation in FKRP, L169P and P89L, respectively. Clinical onset was triggered by viral upper respiratory tract infections. In addition to the common dystrophic pattern with a weak immune histochemical staining for alpha-dystroglycan, muscle biopsy showed inflammatory changes. This was especially striking in one of the patients with up-regulation of MHC class 1 antigen, suggestive of myositis. Both patients showed a good clinical response to treatment with prednisolone, which was initiated at daily dosage of 0.35mg/kg/day. Our results provide evidence for an inflammatory involvement in the pathological expression of LGMD2I and open up the possibility that this disorder could be treatable with corticosteroids.
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| 12. |
- Darin, Niklas, 1964, et al.
(författare)
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Mitochondrial myopathy with exercise intolerance and retinal dystrophy in a sporadic patient with a G583A mutation in the mt tRNA(phe) gene
- 2006
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:8, s. 504-6
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Tidskriftsartikel (refereegranskat)abstract
- We describe a second patient with the 583G>A mutation in the tRNA(phe) gene of mitochondrial DNA (mtDNA). This 17-year-old girl had a mitochondrial myopathy with exercise intolerance and an asymptomatic retinopathy. Muscle investigations showed occasional ragged red fibers, 30% cytochrome c oxidase (COX)-negative fibers, and reduced activities of complex I+IV in the respiratory chain. The mutation was heteroplasmic (79%) in muscle but undetectable in other tissues. Analysis of single muscle fibers revealed a significantly higher level of mutated mtDNA in COX-negative fibers. Our study indicates that the 583G>A mutation is pathogenic and expands the clinical spectrum of this mutation.
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| 13. |
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| 14. |
- Hedberg, Carola, 1969, et al.
(författare)
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Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation.
- 2012
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 1873-2364 .- 0960-8966. ; 22:3, s. 244-51
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated a woman and her daughter with an early onset, slowly progressive myopathy. Muscle biopsy showed in both cases severe atrophy with marked fatty replacement. Frequent fibers with internalized nuclei were present but no typical features of centronuclear myopathy. There were also many fibers with deep invaginations of the plasma membrane. The presence of necklace fibers provided clue to correct genetic diagnosis. Both patients had a novel heterozygous splice site mutation in the myotubularin gene, MTM1 (c.867+1G>T). Analysis of MTM1 cDNA revealed that the mutation resulted in aberrant splicing with variable exon skipping. The expression of normal transcripts was markedly reduced and there was reduced expression of myotubularin protein. Although the expression of the allele without the mutation was reduced we did not obtain evidence of skewed X-chromosome inactivation. Other factors than skewed X-inactivation may cause allele inactivation and manifestation of severe myopathy in heterozygous carriers of pathogenic MTM1 mutations.
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| 15. |
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| 16. |
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| 17. |
- Horvath, Rita, et al.
(författare)
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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
- 2009
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 132:Pt 11, s. 3165-74
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Tidskriftsartikel (refereegranskat)abstract
- Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
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| 18. |
- 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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| 19. |
- 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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| 20. |
- 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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| 21. |
- Kollberg, Gittan, 1963, et al.
(författare)
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A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion.
- 2009
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Ingår i: Neuromuscular disorders : NMD. - : Elsevier BV. - 0960-8966. ; 19:2, s. 147-50
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Tidskriftsartikel (refereegranskat)abstract
- This report describes two brothers, both deceased in infancy, with severe depletion of mitochondrial DNA (mtDNA) in muscle tissue. Both had feeding difficulties, failure to thrive, severe muscular hypotonia and lactic acidosis. One of the boys developed a renal proximal tubulopathy. A novel homozygous c.686 G-->T missense mutation in the RRM2B gene, encoding the p53-inducible ribonucleotide reductase subunit (p53R2), was identified. This is the third report on mutations in RRM2B associated with severe mtDNA depletion, which further highlights the importance of de novo synthesis of deoxyribonucleotides (dNTPs) for mtDNA maintenance.
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| 22. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations.
- 2005
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 13:4, s. 463-9
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial myopathy in progressive external ophthalmoplegia (PEO) has been associated with POLG1 mutations. POLG1 encodes the catalytic alpha subunit of polymerase gamma and is the only polymerase known to be involved in mtDNA replication. It has two functionally different domains, one polymerase domain and one exonuclease domain with proofreading activity. In this study we have investigated whether mtDNA point mutations are involved, directly or indirectly, in the pathogenesis of PEO. Muscle biopsy specimens from patients with POLG1 mutations, affecting either the exonuclease or the polymerase domain, were investigated. Single cytochrome c oxidase (COX)-deficient muscle fibers were dissected and screened for clonally expanded mtDNA point mutations using a sensitive denaturing gradient gel electrophoresis analysis, in which three different regions of mtDNA, including five different tRNA genes, were investigated. To screen for randomly distributed mtDNA point mutations in muscle, two regions of mtDNA including deletion breakpoints were investigated by high-fidelity PCR, followed by cloning and sequencing. Long-range PCR revealed multiple mtDNA deletions in all the patients but not the controls. No point mutations were identified in single COX-deficient muscle fibers. Cloning and sequencing of muscle homogenate identified randomly distributed point mutations at very low frequency in patients and controls (<1:50 000). We conclude that mtDNA point mutations do not appear to be directly or indirectly involved in the pathogenesis of mitochondrial disease in patients with different POLG1 mutations.
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| 23. |
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| 24. |
- Kollberg, Gittan, 1963, et al.
(författare)
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Mitochondrial myopathy and rhabdomyolysis associated with a novel nonsense mutation in the gene encoding cytochrome c oxidase subunit I.
- 2005
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Ingår i: Journal of neuropathology and experimental neurology. - 0022-3069. ; 64:2, s. 123-8
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial DNA (mtDNA) mutations associated with rhabdomyolysis are rare but have been described in sporadic cases with mutations in the cytochrome b and cytochrome c oxidase (COX) genes and in 3 cases with tRNALeu mutation. We report a novel heteroplasmic G6708A nonsense mutation in the mtDNA COI gene encoding COX subunit I in a 30-year-old woman with muscle weakness, pain, fatigue, and one episode of rhabdomyolysis. Histochemical examination of muscle biopsy specimens revealed reduced COX activity in the majority of the muscle fibers (approximately 90%) and frequent ragged red fibers. Biochemical analysis showed a marked and isolated COX deficiency. Analysis of DNA extracted from single fibers revealed higher levels of the mutation in COX-deficient fibers (> 95%) compared with COX-positive fibers (1%-80%). The mutation was not detected in a skin biopsy, cultured myoblasts, or blood leukocytes. Nor was it identified in blood leukocytes from the asymptomatic mother, indicating a de novo mutation that arose after germ layer differentiation. Western blot analysis and immunohistochemical staining revealed that reduced levels of COX subunit I were accompanied by reduced levels of other mtDNA encoded subunits, as well as nuclear DNA encoded subunit IV, supporting the concept that COX subunit I is essential for the assembly of complex IV in the respiratory chain.
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| 25. |
- Kollberg, Gittan, 1963, et al.
(författare)
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POLG1 mutations associated with progressive encephalopathy in childhood.
- 2006
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Ingår i: Journal of neuropathology and experimental neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 65:8, s. 758-68
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Tidskriftsartikel (refereegranskat)abstract
- We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.
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