The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy
Highlights
► We reported a patient with Wolfram syndrome and dilated cardiomyopathy. ► We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). ► Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. ► The deletions remove several tRNA and protein-coding genes.
Introduction
First described in 1938, Wolfram syndrome (WFS) (MIM 222300) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) [1], [2]. This is a progressive, neurodegenerative disorder, with diabetes mellitus and optic atrophy presenting in the first decade, cranial diabetes insipidus, and sensorineural deafness in the second, and neuropathic bladder in the third, followed by neurological complications in the fourth decade [3], [4].
Nevertheless, such manifestations are not always present and we can note the association with other diverse neurological and psychiatric features, including ataxia, peripheral neuropathy, dementia and depression. Thus, Wolfram syndrome seems to be a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult because, with the exception of a few series, the number of patients in most reports is small. The pathogenesis of the disease is still unknown.
Diagnosis is usually established in one or several siblings from unaffected parents suggesting an autosomal recessive mode of transmission [5]. In fact, one candidate gene WFS1 (wolframin) has been mapped to chromosome 4p and was recently cloned and localized [6], [7], [8]. It was shown to encode a transmembrane protein called wolframin whose function is not yet determined.
Nevertheless, the wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. This hypothesis was confirmed in sporadic cases that showed a loss of mitochondrial function and the presence of heteroplasmic deletion in mtDNA [9], [10], [11]. In addition, authors suggested that mtDNA variants (4216 and 11,251) may predispose to Wolfram syndrome [12].
In the present study, we report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. His brother was died from a typical Wolfram syndrome since he suffered from diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. The mitochondrial DNA genetic study in the alive patient revealed the presence of the ND1 m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle) but also multiple mitochondrial deletions in the DNA extracted from the skeletal muscle.
Section snippets
Patient
The proband is a 36 years-old men presented with type II diabetes, neurological complications and dilated cardiomyopathy. He had steppage gait and his Magnetic Resonance Imaging (MRI) showed localized dilatation of the left occipital horn with hyperintense white matter on T2 but without any abnormalities on the brainstem and the cerebellum. His eye fundus examination did not show optic atrophy or retinitis pigmentosa and his audiogram was normal.
His brother died from a typical Wolfram syndrome
Results
In the present study, we reported a 36-years-old men patient with type II diabetes, neurological complications and dilated cardiomyopathy. He presented steppage gait and his MRI showed hyperintense white matter on T2. His brother was died from a typical Wolfram syndrome.
We started the genetic study by a mutational screening of the mitochondrial genes associated to diabetes. In fact, we screened the tRNALeu(UUR) and the tRNAGlu genes, but no reported mutations were found, especially the
Discussion
We reported a 36 years-old men presenting with type II diabetes, neurological complications, dilated cardiomyopathy and an MRI showing localized dilatation of the left occipital horn with hyperintense white matter on T2 but without any abnormalities on the brainstem and the cerebellum. His brother was died from a typical Wolfram syndrome suggesting that the studied patient presents a moderate form of Wolfram syndrome.
A study of the mitochondrial DNA showed the presence of the ND1 m.3337G>A
Acknowledgments
We thank the patient and his family for their cooperation in the present study. This work was supported by The Ministry of Higher Education and Scientific Research in Tunisia.
References (20)
- et al.
Juvenile diabetes mellitus, optic atrophy, sensory nerve deafness, and diabetes insipidus: a syndrome
J. Pediatr.
(1976) - et al.
A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome)
Nat. Genet.
(1998) - et al.
Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q
Am. J. Hum. Genet.
(2000) - et al.
Mutational analysis of the mitochondrial tRNALeu(UUR) gene in Tunisian patients with mitochondrial diseases
Biochem. Biophys. Res. Commun.
(2007) - et al.
A novel G3337A mitochondrial ND1 mutation related to cardiomyopathy co-segregates with tRNALeu(CUN) A12308G and tRNAThr C15946T mutations
Mitochondrion
(2008) - et al.
A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy
Am. Coll. Cardiol.
(2003) - et al.
Clinical and molecular findings in children with complex I deficiency
Biochim. Biophys. Acta
(2004) - et al.
Diabetes mellitus, simple optic atrophy among siblings: report of four cases
Mayo Clin. Proc.
(1938) - et al.
Juvenile diabetes mellitus, optic atrophy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder, and other abnormalities (Wolfram syndrome)
Acta Paediatr. Scand.
(1977) - et al.
Recessive inheritance of diabetes: the syndrome of diabetes insipidus, diabetes mellitus, optic atrophy and deafness
Q. J. Med.
(1976)
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Wolframin deficiency is accompanied with metabolic inflexibility in rat striated muscles
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First description of a novel mitochondrial mutation in the MT-TI gene associated with multiple mitochondrial DNA deletion and depletion in family with severe dilated mitochondrial cardiomyopathy
2018, Biochemical and Biophysical Research CommunicationsCitation Excerpt :In addition, to the punctual mitochondrial mutations, mitochondrial cardiomyopathy were also but rarely associated with larger mtDNA rearrangements and abnormal reduction in mtDNA content representing mtDNA depletion [12]. Thus, deletions were reported associated with dilated cardiomyopathy [13,14]. However, mtDNA depletion causes heterogeneous group of severe and usually lethal diseases in infancy and childhood like for instance neonates and infants mitochondrial cardiomyopathy [15,16].
Cardiac manifestations of primary mitochondrial disorders
2014, International Journal of CardiologyA maternally inherited diabetes and deafness patient with the 12S rRNA m.1555A>G and the ND1 m.3308T>C mutations associated with multiple mitochondrial deletions
2013, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Thus, it affects the ND1 protein, an important mitochondrial enzyme and a component of complex I, which is responsible for electron transfer from NADH to ubiquinone. Besides, it was reported that mutations in ND1 gene were related to mitochondrial diseases such as diabetes and cardiomyopathy [36–38]. The m.3308T>C mutation was described in patients with MELAS [39,40].
A novel m.12908T>A mutation in the mitochondrial ND5 gene in patient with infantile-onset Pompe disease
2012, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The similarity of phenotypes observed in Pompe disease and in several mitochondrial cytopathies suggests the implication of mitochondrial DNA in patient with Pompe disease. In fact, mitochondrial mutations could be detected in several autosomal recessive diseases such as Wolfram syndrome [8–11]. In this study, we reported a novel m.12908T>A mitochondrial mutation (p.191L>Q) in the NADH–dehydrogenase subunit 5 (ND5) gene, in patient with clinical features of Pompe disease particularly with a hypertrophic cardiomyopathy, a hypotonia and a hepatomegaly.