Mitochondrial Fission Factor Gene Mutation: A Dilemma for Prenatal Diagnosis
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ABSTRACT:
SUBMITTER: Sharma C
PROVIDER: S-EPMC8061609 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease.
| S-EPMC2891719 | biostudies-literature
Project description:Familial cerebellar ataxia with hydrocephalus in Bullmastiffs was described almost 40 years ago as a monogenic autosomal recessive trait. We investigated two young Bullmastiffs showing similar clinical signs. They developed progressive gait and behavioural abnormalities with an onset at around 6 months of age. Neurological assessment was consistent with a multifocal brain disease. Magnetic resonance imaging of the brain showed intra-axial bilateral symmetrical focal lesions localised to the cerebellar nuclei. Based on the juvenile age, nature of neurological deficits and imaging findings, an inherited disorder of the brain was suspected. We sequenced the genome of one affected Bullmastiff. The data were compared with 782 control genomes of dogs from diverse breeds. This search revealed a private homozygous frameshift variant in the MFF gene in the affected dog, XM_038574000.1:c.471_475delinsCGCTCT, that is predicted to truncate 55% of the wild type MFF open reading frame, XP_038429928.1: p.(Glu158Alafs*14). Human patients with pathogenic MFF variants suffer from 'encephalopathy due to defective mitochondrial and peroxisomal fission 2'. Archived samples from two additional affected Bullmastiffs related to the originally described cases were obtained. Genotypes in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect segregation with the disease phenotype. The available data together with information from previous disease reports allow classification of the investigated MFF frameshift variant as pathogenic and probably causative defect of the observed neurological phenotype. In analogy to the human phenotype, we propose to rename this disease 'mitochondrial fission encephalopathy (MFE)'.
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Project description:OBJECTIVE:To investigate the mutation of related genes and prenatal diagnosis of a family with Bartter syndrome (BS). METHODS:The high-throughput capture sequencing technique and PCR-Sanger sequencing were used to detect pathogenic genes in the proband of this family and analyze the whole family at the genomic level. After the genetic cause was clarified, the amniotic fluid was collected from the proband's mother who was pregnant for 5 months for prenatal diagnosis. RESULTS:The proband carried compound heterozygous mutations of c.88C>T(p.Arg30*) and c.968+2T>A in the CLCNKB gene; c.88C>T(p.Arg30*) had been reported as a pathogenic mutation, and c.968+2T>A was a new mutation. Pedigree analysis showed that the two mutations were inherited from the mother and father, respectively. Prenatal diagnosis showed that the fetus did not inherit the mutations from parents and had no mutations at the two loci. The follow-up visit confirmed that the infant was in a healthy state, which proved the accuracy of genetic diagnosis and prenatal diagnosis. CONCLUSIONS:The compound heterozygous mutations c.88C>T(p.Arg30*) and c.968+2T>A in the CLCNKB gene are the cause of BS in the proband, and prenatal diagnosis can prevent the risk of recurrence of BS in this family.
| S-EPMC7399506 | biostudies-literature
Project description:Mitochondrial Fission Factor (MFF) is part of a protein complex that promotes mitochondria and peroxisome fission. Hitherto, only 5 patients have been reported harboring mutations in MFF, all of them with the clinical features of a very early onset Leigh-like encephalopathy. We report on an 11-year-old boy with epileptic encephalopathy. He presented with neurological regression, epileptic myoclonic seizures, severe intellectual disability, microcephaly, tetraparesis, optic atrophy, and ophthalmoplegia. Brain MRI pattern was compatible with Leigh syndrome. NGS-based analysis of a gene panel for mitochondrial disorders revealed a homozygous c.892C>T (p. Arg298*) in the MFF gene. Fluorescence staining detected abnormal morphology of mitochondria and peroxisomes in fibroblasts from the patient; a strong reduction in MFF protein levels and the presence of truncated forms were observed. No biochemical alterations denoting peroxisomal disorders were found. As reported in other disorders affecting the dynamics of intracellular organelles, our patient showed clinical features suggesting both mitochondrial and peroxisomal impairment. High levels of lactate in our case suggested an involvement of the energetic metabolism but without clear respiratory chain deficiency, while biomarkers of peroxisomal dysfunction were normal. We confirm that MFF mutations are associated with epileptic encephalopathy with Leigh-like MRI pattern.
| S-EPMC6292958 | biostudies-literature
Project description:BackgroundChiari malformation is one of the most common Central nervous system (CNS) abnormalities that can be detected in routine fetal scanning. Chiari malformation type I (CMI) is a congenital defect characterized by a displacement of the cerebellar tonsils through the foramen magnum. The etiology of CMI has not been well established and suggested having multifactorial contributions, especially genetic deletion. Clinical characteristics of this anomaly may express in different symptoms from neurological dysfunction and/or skeletal abnormalities in the later age, but it is rarely reported in pregnancy.Case presentationWe present a case in which the Chiari malformation type I was diagnosed with comorbidities of facial anomalies (flatting forehead and micrognathia) and muscular-skeletal dysmorphologies (clenched hands and clubfeet) at the 24+6 weeks of gestation in a 29-year-old Vietnamese pregnant woman. The couple refused an amniocentesis, and the pregnancy was followed up every 4 weeks until a spontaneous delivery occurred at 38 weeks. The newborn had a severe asphyxia and seizures at birth required to have an emergency resuscitation at delivery. He is currently being treated in the intensive neonatal care unit. He carries the novel heterozygous NFIA gene mutation confirmed after birth. No further postnatal malformation detected.ConclusionCMI may only represent with facial abnormalities and muscle-skeletal malformations at the early stage of pregnancy, which may also alert an adverse outcome. A novel heterozygous NFIA gene mutation identified after birth helps to confirm prenatal diagnosis of CMI and to provide an appropriate consultation.
| S-EPMC10863238 | biostudies-literature
Project description:This study aimed to identify the type of carnitine palmitoyltransferase 2 (CPT2) gene mutation in the child with carnitine palmitoyltransferase II (CPT II) deficiency and her parents and to provide the genetic counseling and prenatal diagnosis for the family members. As the proband, a 3-month-old female baby was admitted to the hospital due to fever which had lasted for 8 hours. Tandem mass spectrometric analysis for blood showed an elevated plasma level of acylcarnitine, which suggested CPT II deficiency. The genomic DNA was extracted from peripheral blood of the patient and her parents. Five exon coding regions and some intron regions at the exon/intron boundaries of the CPT2 gene were analyzed by PCR and Sanger sequencing. Amniotic fluid was taken from the mother during the second trimester, and DNA was extracted to analyze the type of CPT2 gene mutation. Sanger sequencing results showed that two mutations were identified in the CPT2 gene of the proband: c.886C>T (p.R296X) and c.1148T>A (p.F383Y), which were inherited from the parents; the second child of the mother inherited the mutation of c.886C>T (p.R296X) and showed normal acylcarnitine spectrum and normal development after birth. It is concluded that the analysis of CPT2 gene mutations in the family suggested that the proband died of CPT II deficiency and that the identification of the mutations was helpful in prenatal diagnosis in the second pregnancy.
| S-EPMC7403082 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the most common primary liver tumor and one of the leading causes of cancer-related death worldwide. Chemotherapeutic agents/regimens such as cisplatin (DDP) are frequently used for advanced HCC treatment. However, drug resistance remains a major hindrance and the underline mechanisms are not fully understood. In this study, we investigated the expression pattern and function of mitochondrial fission factor (Mff) in cisplatin-resistant HCC. We found that Mff is highly expressed in cisplatin-resistant HCC tissues and cell lines. Knockdown of Mff suppresses cell proliferation and promotes cell apoptosis of HCC/DDP cells. In addition, knockdown of Mff sensitizes Huh-7/DDP cells to cisplatin treatment, inhibits cell proliferation, migration and invasion, and enhances cell apoptosis. Confocal imaging showed that knockdown of Mff inhibits the mitochondrial fission and downregulates the expression of GTPase dynamin-related protein 1 (Drp1) in cisplatin-resistant Huh-7/DDP cells. Moreover, xenograft tumor model revealed that knockdown of Mff sensitizes Huh-7/DDP xenograft tumor to cisplatin treatment . In summary, our findings suggest that Mff regulates mitochondrial Drp1 expression and promotes cisplatin resistance in HCC, which provides a potential therapeutic target for the treatment of resistant HCC.
| S-EPMC9828151 | biostudies-literature
Project description:Prenatal diagnoses of mitochondrial diseases caused by defects in nuclear DNA (nDNA) or mitochondrial DNA have been reported in several countries except for Japan. The present study aimed to clarify the status of prenatal genetic diagnosis of mitochondrial diseases caused by nDNA defects in Japan. A comprehensive genomic analysis was performed to diagnose more than 400 patients, of which, 13 families (16 cases) had requested prenatal diagnoses. Eight cases diagnosed with wild type homozygous or heterozygous variants same as either of the heterozygous parents continued the pregnancy and delivered healthy babies. Another eight cases were diagnosed with homozygous, compound heterozygous, or hemizygous variants same as the proband. Of these, seven families chose to terminate the pregnancy, while one decided to continue the pregnancy. Neonatal- or infantile-onset mitochondrial diseases show severe phenotypes and lead to lethality. Therefore, such diseases could be candidates for prenatal diagnosis with careful genetic counseling, and prenatal testing could be a viable option for families.
| S-EPMC7878886 | biostudies-literature
Project description:BackgroundPatients with Duchenne muscular dystrophy (DMD) usually have severe and fatal symptoms. At present, there is no effective treatment for DMD, thus it is very important to avoid the birth of children with DMD by effective prenatal diagnosis. We identified a de novo DMD gene mutation in a Chinese family, and make a prenatal diagnosis.MethodsFirst, multiplex ligation-dependent probe amplification (MLPA) was applied to analyze DMD gene exon deletion/duplication in all family members. The coding sequences of 79 exons in DMD gene were analyzed by Sanger sequencing in the patient; and then according to DMD gene exon mutation in the patient, DMD gene sequencing was performed in the family members. On the basis of results above, the pathogenic mutation in DMD gene was identified.ResultsMLPA showed no DMD gene exon deletion/duplication in all family members. Sanger sequencing revealed c.2767_2767delT [p.Ser923LeufsX26] mutation in DMD gene of the patient. Heterozygous deletion mutation (T/-) at this locus was observed in the pregnant woman and her mother and younger sister. The analyses of amniotic fluid samples indicated negative Y chromosome sex-determining gene, no DMD gene exon deletion/duplication, no mutations at c.2767 locus, and the inherited maternal X chromosome different from that of the patient.ConclusionThe pathogenic mutation in DMD gene, c.2767_2767delT [p.Ser923LeufsX26], identified in this family is a de novo mutation. On the basis of specific conditions, it is necessary to select suitable methods to make prenatal diagnosis more effective, accurate, and economic.
| S-EPMC5815683 | biostudies-literature
Project description:BACKGROUND The aim of this study was to perform gene detection in 2 clinical cases of highly suspected ornithine transcarbamylase deficiency (OTCD) pediatric patients by first-generation sequencing technology in order to confirm the pathogenic genetic factors of their families and allow the families to undergo genetic counselling and prenatal diagnosis. MATERIAL AND METHODS The peripheral DNA samples of 2 children with highly suspected OTCD (the probands) and their parents were collected. DNA fragments corresponding to exons 1-10 of the OTC gene from the samples were amplified using polymerase chain reaction (PCR), and then subjected to Sanger sequencing to confirm the pathogenic mutation sites. RESULTS The probands were both confirmed to have OTCD. The proband in Family 1 was a male carrying a c.867+1G>C mutation at a splice site within the OTC gene. The gene detection results of amniotic fluid cells at 16 weeks of pregnancy showed that the fetus was a male who also carried the c.867+1G>C mutation. The proband in Family 2 was a male carrying a c.782T>C(p. I261T) mutation in the OTC gene. The gene detection results of amniotic fluid cells at 18 weeks showed that the fetus was a male without pathogenic mutations in the OTC gene. The gene detection results of peripheral blood from the fetus after birth were consistent with those obtained from amniotic fluid cells. CONCLUSIONS Pediatric children who are clinically suspected of OTCD can receive a definitive diagnosis through OTC gene detection.
| S-EPMC6354644 | biostudies-literature