A Lethal Defect of Mitochondrial and Peroxisomal Fission  

Oleh:

Waterham, Hans R. ; Koster, Janet ; Roermund, Carlo W.T. van ; Mooyer, Petra A.W. ; Wanders, Ronald J.A. ; Leonard, James V.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: The New England Journal of Medicine (keterangan: ada di Proquest) vol. 356 no. 17 (Apr. 2007), page 1736.

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Perpustakaan FK Nomor Panggil: N08.K.2007.02 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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SUMMARY We report on a newborn girl with microcephaly, abnormal brain development, optic atrophy and hypoplasia, persistent lactic acidemia, and a mildly elevated plasma concentration of very-long-chain fatty acids. We found a defect of the fission of both mitochondria and peroxisomes, as well as a heterozygous, dominant-negative mutation in the dynamin-like protein 1 gene (DLPl). The DLPl protein has previously been implicated, in vitro, in the fission of both these organelles. Overexpression of the mutant DLPI in control cells reproduced the fission defect. Our findings are representative of a class of disease characterized by defects in both mitochondria and peroxisomes. HE EUKARYOTIC CELL MUST CONTROL THE FUSION AND FISSION OF ITS organelles to maintain an ordered and dynamic subcellular organization. Key proteins in these processes are members of the dynamin superfamily of ; large, conserved guanosine triphosphatases (GTPases) that participate in various cellular processes, including the fission of mitochondria and peroxisomes.1,2 Three : autosomal dominant neuropathies have been linked to mutations in three separate , dynamin genes.3's We describe a newborn girl with a lethal disorder and a dominant¬ , negative mutation in a fourth dynamin gene, which encodes dynamin-like protein 1 (DLPl). The mutation is associated with a severe defect in the fission of both mito¬ . chondria and peroxisomes. CASE REPORT The female infant was born at term by vaginal delivery to nonconsanguineous, healthy parents of white British ancestry. During the pregnancy, the mother noted diminished fetal movements. The birth weight was 2.78 kg. The infant initially ap¬peared well and was discharged after 4 days, but she was readmitted 2 days later because of poor feeding and concern that she was unusually quiet. Her weight was 2.58 kg and she appeared mildly dysmorphic, with deep-set eyes, a pointed chin, and a head circumference below the 0.4 percentile. She had truncal hypotonia with little spontaneous movement and no tendon reflexes. She did not respond to light stimulation, she had horizontal nystagmus with poor visual fixation, and her optic disks were pale and cupped. Magnetic resonance imaging of the brain revealed an abnormal gyral pattern in both frontal lobes that extended to the perisylvian areas and was associated with dysmyelination. Electromyography, echo cardiography, and nerve-conduction studies

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