Hannu Somer

Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria

The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.

Muscle-eye-brain disease (MEB)

Clinical features of a rare congenital myopathy, muscle-eye-brain (MEB) disease, are described in 19 patients. The pedigree data suggest an autosomal recessive inheritance. The patients presented with congenital hypotonia and muscle weakness. Serum CK was elevated, EMG was myopathic and muscle biopsy showed slight or moderate changes compatible with muscular dystrophy. Ophthalmological findings included severe visual failure and uncontrolled eye movements associated with severe myopia. The flash VEPs were exceptionally high, whereas non-corneal ERG was unrecordable. The EEG showed progressive abnormalities after the age of 6 months. Psychomotor development was slow during the first years of life, and mental retardation was severe. Most patients began to deteriorate around age 5 years. This change included spasticity and joint contractures. CT scans showed ventricular dilatations and abnormally low white matter density in several patients. Spasticity, high VEPs and ocular manifestations differentiate MEB from the Fukuyama type congenital muscular dystrophy.

Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia.

Multiple deletions of mitochondrial DNA (mtDNA) have recently been reported in familial progressive external ophthalmoplegia (PEO), in a case of progressive encephalomyopathy, and in inherited recurrent myoglobinuria. The inheritance of familial PEO has been autosomal dominant, which indicates that a mutation in an unknown nuclear gene results in several mtDNA deletions of different sizes in these patients. We report a patient with autosomal dominant PEO, whose major clinical symptom, however, was severe retarded depression. The morphological analyses of the tissue samples derived from autopsy showed various abnormalities in the mitochondria in all the tissues studied. The activities of the respiratory chain enzymes encoded by mtDNA were remarkably reduced in the skeletal muscle. The mtDNA analyses confirmed that besides myopathy, this patient had a multisystem disorder with widespread distribution of multiple deletions of mtDNA. The highest percentage of mutated mtDNA was found in the brain, skeletal muscle and the heart, the relative quantity of mutated mtDNA correlating to the severity of the clinical symptoms.

The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone.

We identified the gene underlying Marinesco-Sjögren syndrome, which is characterized by cerebellar ataxia, progressive myopathy and cataracts. We identified four disease-associated, predicted loss-of-function mutations in SIL1, which encodes a nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5. These data, together with the similar spatial and temporal patterns of tissue expression of Sil1 and Hspa5, suggest that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjögren syndrome.

Inherited idiopathic dilated cardiomyopathy with multiple deletions of mitochondrial DNA.

Idiopathic dilated cardiomyopathy (DCM) is often familial, but the pathogenetic mechanisms of DCM are unknown. We report a woman and her son who both died of DCM. The sons cardiac and skeletal muscles showed a high proportion of mitochondrial DNA (mtDNA) with multiple large deletions by Southern-blot hybridisation and polymerase chain reaction analyses. Amplification of the mothers cardiac mtDNA from 20-year-old paraffin-embedded sections showed that she also had deletions of mtDNA. These data suggest that a subgroup of inherited DCMs is associated with mtDNA mutations.

Determination of serum creatine kinase isoenzymes in myocardial infarction

Abstract Serum creatine kinase (CK) isoenzymes were measured in patients with acute myocardial infarction by an improved method which allows quantitation of CK isoenzymes in the serum. Since there are no previous reports of the serum CK isoenzyme pattern in myocardial infarction, the study was focused on uncomplicated myocardial infarction. This was done in order to obtain information of the “heart pattern” of serum CK isoenzyme activity. The principal increase was found to depend on increases in skeletal muscle (MM) isoenzymes and, to a lesser degree, on augmentation of myocardial (MB) isoenzymes.

Amyloid protein in familial amyloidosis (Finnish type) is homologous to gelsolin, an actin-binding protein

Familial amyloidosis, Finnish type, is clinically characterized by cranial neuropathy and lattice corneal dystrophy. It is an autosomal dominant form of systemic amyloidosis with small deposits of congophilic material occurring in most tissues, particularly in association with blood vessel walls and basement membranes. Amyloid fibrils were extracted from the kidney of patient VUO, and rabbit antiserum raised against the 12 kDa purified amyloid subunit displayed strong immunohistochemical reactivity with the amyloid deposits. The amino terminal sequence of this 12 kDa amyloid protein (ATEVPVSWESFNNGD) showed homology with gelsolin (or actin depolymerizing factor), a 93 kDa plasma protein. The amyloid peptide is a degradation product, starting at position 173, of the gelsolin molecule.

Creatine kinase isoenzymes in neuromuscular diseases

Determination of the creatine kinase isoenzyme pattern in 62 biopsy samples obtained from patients with neuromuscular disease revealed changes mainly in Duchenne muscular dystrophy. The BB isoenzyme was detected in 10 out of 17 cases with Duchenne muscular dystrophy and the relative amount of MB+BB isoenzyme was significantly increased in this group (P less than 0.005). In serum the MB isoenzyme was detected in all 28 cases with progressive muscular dystrophy and frequently also in other neuromuscular diseases. Among 152 control samples the MB isoenzyme was detected only in 2 cases. It is suggested that the finding of MB isoenzyme in the serum with normal or only slightly elevated total CK activity may be a further proof of neuromuscular disorder, but the finding is not specific for any particular disease.

Demonstration of serum creatine kinase isoenzymes by fluorescence technique

Abstract Serum creatine kinase (CK) isoenzymes can be sensitively and specifically demonstrated by the fluorescence of NADPH2. The method allows demonstration over the whole normal range. The technique is more specific than the tetrazolium staining methods because the “nothing dehydrogenase reaction” does not cause disturbing artefacts as in the staining methods.

Heart type creatine kinase isoenzyme (CK MB) in acute cerebral disorders.

Heart type creatine kinase isoenzyme (CK MB) was detected in the serum in 23 out of 53 patients (43%) with acute cerebrovascular, traumatic, or infectious brain damage. Electrocardiogram disclosed abnormalities suggestive of acute myocardial injury in 15 of these 23 patients. Eleven of them also showed increased LD1 activity. Subendocardial haemorrhage was detected in 3 out of 8 necropsied patients with serum CK MB activity. Among those 30 patients in whom no CK MB activity was found electrocardiographic abnormalities suggestive of acute myocardial injury were observed in 2 and increased LD1 was seen in 4 cases. The mortality was higher if either CK MB isoenzyme or electrocardiographic abnormalities suggestive of acute myocardial injury were present, compared with the patients lacking these signs (P less than 0.01). Present findings suggest that acute brain damage may secondarily cause myocardial damage more often than has been believed before. Results also indicate that a combination of acute brain damage and acute myocardial injury often indicated a poor prognosis.