A GPHN point mutation leading to molybdenum cofactor deficiency

Reiss, Jochen; Lenz, U; Aquaviva-bourdain, Cécile; Joriot-Chekaf, S; Mention-Mulliez, Karine; Holder‐Espinasse, Muriel

doi:10.1111/j.1399-0004.2011.01709.x

Cited by 35 publications

(30 citation statements)

References 10 publications

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“…A second case with missense mutation in GEPH affects an invariant aspartate residue (Asp580) within the active site of the GEPHYRIN E-domain. This patient presented typical symptoms of MoCD, was two years old at the time of report [ 138 ] with severe axial hypotonia, peripheral hypertonia, and lack of head control and visual contact. Based on the clinical presentation as well as the underlying genetic defect, one can assume that in this patient Moco synthesis, namely the hydrolysis of MPT-AMP and molybdenum insertion is prohibited while GEPHYRIN's function in receptor clustering is retained given that the binding site of both, glycine [ 139 ] and GABA receptors [ 140 ] are distinct from Moco synthesis [ 113 ].…”

Section: Mutations In Molybdenum Cofactor-defi Cient Patientsmentioning

confidence: 95%

“…However, this reaction is only possible, when MPT is present in high quantities, while MPT-AMP, the reaction product of the G domain of gephyrin cannot be activated by molybdate. Therefore, the second gephyrin patient carrying a point mutation within the E-domain [ 138 ] would not have benefi ted from molybdate substitution therapy. In conclusion, we propose that gephyrin patients with missense mutation within the G-domain that do not impair the synaptic function of gephyrin, should be considered for molybdate supplementation.…”

Section: Treatment Of Mocd Type B and C Patientsmentioning

confidence: 98%

“…Since then more than 100 cases with MoCD have been reported [ 77 , 134 ], which nearly all share a predominant deterioration of the central nervous system as main disease feature mimicking hypoxic ischemic encephalopathy during the fi rst days of presentation [ 146 ]. In general, fi rst symptoms are observed within the fi rst days of life, which are initially presented by feeding diffi culties accompanied with intractable seizures with a predominant opisthotonus and an exaggerated startle reaction [ 138 ]. Disease progression is accompanied by psychomotor retardation due to progressive cerebral atrophy and ventricular dilatation, which are typical in brain MRI of patients (Figure 4b ).…”

Section: Clinical Presentation Of Patients With Molybdenummentioning

confidence: 98%

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Molybdenum in Human Health and Disease

Schwarz

Belaidi

2013

Metal Ions in Life Sciences

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Molybdenum is an essential trace element and crucial for the survival of animals. Four mammalian Mo-dependent enzymes are known, all of them harboring a pterin-based molybdenum cofactor (Moco) in their active site. In these enzymes, molybdenum catalyzes oxygen transfer reactions from or to substrates using water as oxygen donor or acceptor. Molybdenum shuttles between two oxidation states, Mo(IV) and Mo(VI). Following substrate reduction or oxidation, electrons are subsequently shuttled by either inter- or intra-molecular electron transfer chains involving prosthetic groups such as heme or iron-sulfur clusters. In all organisms studied so far, Moco is synthesized by a highly conserved multi-step biosynthetic pathway. A deficiency in the biosynthesis of Moco results in a pleitropic loss of all four human Mo-enzyme activities and in most cases in early childhood death. In this review we first introduce general aspects of molybdenum biochemistry before we focus on the functions and deficiencies of two Mo-enzymes, xanthine dehydrogenase and sulfite oxidase, caused either by deficiency of the apo-protein or a pleiotropic loss of Moco due to a genetic defect in its biosynthesis. The underlying molecular basis of Moco deficiency, possible treatment options and links to other diseases, such as neuropsychiatric disorders, will be discussed.

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Section: Mutations In Molybdenum Cofactor-defi Cient Patientsmentioning

confidence: 95%

Section: Treatment Of Mocd Type B and C Patientsmentioning

confidence: 98%

Section: Clinical Presentation Of Patients With Molybdenummentioning

confidence: 98%

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Molybdenum in Human Health and Disease

Schwarz

Belaidi

2013

Metal Ions in Life Sciences

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“…107 DISEASE IMPLICATIONS OF GEPHYRIN Some neurological disorders have been linked to gephyrin dysfunctions (e.g., stiff-person syndrome (Moersch-Woltman), hyperekplexia, temporal lobe epilepsy, molybdenum cofactor deficiency, autism and schizophrenia). [108][109][110][111][112][113] These diseases may be partly attributed to defects in the glycinergic system, which can be easily understood given the role of gephyrin in GlyR clustering. Gephyrin levels are reduced in the brains of patients suffering from Alzheimer's disease, but its direct involvement in this disorder has not yet been fully explored.…”

Section: Synaptic Functions Of Gephyrinmentioning

confidence: 99%

Gephyrin: a central GABAergic synapse organizer

2015

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Gephyrin is a central element that anchors, clusters and stabilizes glycine and γ-aminobutyric acid type A receptors at inhibitory synapses of the mammalian brain. It self-assembles into a hexagonal lattice and interacts with various inhibitory synaptic proteins. Intriguingly, the clustering of gephyrin, which is regulated by multiple posttranslational modifications, is critical for inhibitory synapse formation and function. In this review, we summarize the basic properties of gephyrin and describe recent findings regarding its roles in inhibitory synapse formation, function and plasticity. We will also discuss the implications for the pathophysiology of brain disorders and raise the remaining open questions in this field.

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“…Although this type C of MoCo deficiency appears to be curable by these means, transgenic mice carrying the plant homologue Cnx1 on a gephyrin-deficient background despite restored MoCo activity showed unchanged early lethality due to the absence of receptor clustering [30]. One MoCodeficient patient with a homozygous point mutation in the E domain of gephyrin was also described [31]. In contrast to the above case, fibroblasts from the latter patient could not be restored by inorganic molybdate.…”

Section: Gphnmentioning

confidence: 80%

Molybdenum Cofactor and Sulfite Oxidase Deficiency

Reiss¹

2016

Mol Biol (Los Angel)

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A universal molybdenum-containing cofactor is necessary for the activity of all eukaryotic molybdoenzymes. In humans four such enzymes are known: Sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase and a mitochondrial amidoxime reducing component. Of these, sulfite oxidase is the most important and clinically relevant one. Mutations in the genes MOCS1, MOCS2 or GPHN -all encoding cofactor biosynthesis proteins -lead to molybdenum cofactor deficiency type A, B or C, respectively. All three types plus mutations in the SUOX gene responsible for isolated sulfite oxidase deficiency lead to progressive neurological disease which untreated in most cases leads to death in early childhood. Currently, only for type A of the cofactor deficiency an experimental treatment is available.

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A GPHN point mutation leading to molybdenum cofactor deficiency

Cited by 35 publications

References 10 publications

Molybdenum in Human Health and Disease

Molybdenum in Human Health and Disease

Gephyrin: a central GABAergic synapse organizer

Molybdenum Cofactor and Sulfite Oxidase Deficiency

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