Molecular pathogenesis of a new glycogenosis caused by a glycogenin-1 mutation.

Nilsson, JohannaGothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology (author)

Glycogenin-1 initiates the glycogen synthesis in skeletal muscle by the autocatalytic formation of a short oligosaccharide at tyrosine 195. Glycogenin-1 catalyzes both the glucose-O-tyrosine linkage and the α1,4 glucosidic bonds linking the glucose molecules in the oligosaccharide. We recently described a patient with glycogen depletion in skeletal muscle as a result of a non-functional glycogenin-1. The patient carried a Thr83Met substitution in glycogenin-1. In this study we have investigated the importance of threonine 83 for the catalytic activity of glycogenin-1. Non-glucosylated glycogenin-1 constructs, with various amino acid substitutions in position 83 and 195, were expressed in a cell-free expression system and autoglucosylated in vitro. The autoglucosylation was analyzed by gel-shift on western blot, incorporation of radiolabeled UDP-(14)C-glucose and nano-liquid chromatography with tandem mass spectrometry (LC/MS/MS). We demonstrate that glycogenin-1 with the Thr83Met substitution is unable to form the glucose-O-tyrosine linkage at tyrosine 195 unless co-expressed with the catalytically active Tyr195Phe glycogenin-1. Our results explain the glycogen depletion in the patient expressing only Thr83Met glycogenin-1 and why heterozygous carriers without clinical symptoms show a small proportion of unglucosylated glycogenin-1.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Klinisk laboratoriemedicin hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Clinical Laboratory Medicine hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
Amino Acid Sequence
Base Sequence
Biocatalysis
Cell-Free System
Chromatography
Gel
Chromatography
Liquid
DNA Primers
Glucose
metabolism
Glucosyltransferases
chemistry
genetics
isolation & purification
Glycogen
biosynthesis
Glycoproteins
chemistry
genetics
isolation & purification
Humans
Molecular Sequence Data
Mutation
Tandem Mass Spectrometry

Halim, AdnanGothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin,Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine(Swepub:gu)xhalad (author)
Moslemi, Ali-RezaGothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology(Swepub:gu)xmosal (author)
Pedersen, Anders,1976Gothenburg University,Göteborgs universitet,Svenskt NMR-centrum vid Göteborgs universitet,Swedish NMR Centre at Göteborg University(Swepub:gu)xpedan (author)
Nilsson, Jonas,1970Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin,Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine(Swepub:gu)xnjoni (author)
Larson, Göran,1953Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin,Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine(Swepub:gu)xlarsg (author)
Oldfors, Anders,1951Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology(Swepub:gu)xoland (author)
Göteborgs universitetInstitutionen för biomedicin, avdelningen för patologi (creator_code:org_t)

In:Biochimica et biophysica acta: Elsevier BV1822:4, s. 493-90006-3002
In:Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease: Elsevier BV1822:4, s. 493-90925-4439

By the author/editor: Nilsson, Johanna; Halim, Adnan; Moslemi, Ali-Rez ...; Pedersen, Anders ...; Nilsson, Jonas, ...; Larson, Göran, 1 ...; show more...; Oldfors, Anders, ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Clinical Laborat ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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