Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome

Jaeken, Jacques; Eijk, H.G. Van; Heul, C. Van Der; Corbeel, L; Eeckels, R; Eggermont, Ephrem

doi:10.1016/0009-8981(84)90059-7

Cited by 260 publications

(125 citation statements)

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“…Isoelectrofocusing (IEF) of serum transferrin was performed as described (Jaeken et al 1984). IEF of serum apolipoprotein C-III was performed as described (Wopereis et al 2003).…”

Section: Methodsmentioning

confidence: 99%

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

et al. 2012

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Three patients belonging to two families presented with a psychomotor-dysmorphism syndrome including postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement. Other features were muscular hypotrophy, fat excess, partial growth hormone deficiency, and, in two of the three patients, episodes of unexplained fever. Additional investigations showed mild to moderate increases of serum transaminases (particularly of aspartate transaminase (AST)), creatine kinase (CK), and lactate dehydrogenase (LDH), as well as decreased coagulation factors VIII, IX, XI, and protein C. Diagnostic work-up revealed a type 2 serum transferrin isoelectrofocusing (IEF) pattern and a cathodal shift on apolipoprotein C-III IEF pointing to a combined N-and O-glycosylation defect. Known glycosylation disorders with similar N-glycan structures lacking galactose and sialic acid were excluded. Through a combination of homozygosity mapping and expression profiling, a deep intronic homozygous mutation (c.792 þ 182G>A) was found in TMEM165 (TPARL) in the three patients. TMEM165 is a gene of unknown function, possibly involved in Golgi proton/calcium transport. Here we present a detailed clinical description of the three patients with this mutation. The TMEM165 deficiency represents a novel type of CDG (TMEM165-CDG). This disorder enlarges the group of CDG caused by deficiencies in proteins that are not specifically involved in glycosylation but that have functions in the organization and homeostasis of the intracellular compartments and the secretory pathway, like COG-CDG and ATP6V0A2-CDG. Abbreviations

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“…Isoelectrofocusing (IEF) of serum transferrin was performed as described (Jaeken et al 1984). IEF of serum apolipoprotein C-III was performed as described (Wopereis et al 2003).…”

Section: Methodsmentioning

confidence: 99%

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

et al. 2012

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“…The loss of N-glycans on transferrin can easily be monitored by isoelectric focusing using few microliters of blood serum. The pediatrician Jaak Jaeken [5] and Helena Stibler [6] were the first to identify CDG patients using serum transferrin isoelectric focusing. The broad application of this simple test has paved the way to the identification of several defects of N-glycosylation.…”

Section: Historical Remarksmentioning

confidence: 99%

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Hennet

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

117

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BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

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“…The iron-saturated serum proteins were diluted five times with water and applied to a hydrated immobiline gel (PAG plate pH 4-6.5; GE Healthcare) and separated in a Multiphore II system (GE Healthcare). Transferrin isoforms were detected after immunofixation with rabbit anti-human transferrin antibody (Dako, Germany) and Coomassie blue staining (Jaeken et al 1984;Stibler and Jaeken 1990). The relative amounts of the transferrin isoforms were determined and quantified using the Image J 1.42q Software (Wayne Rasband National Institutes of Health, USA).…”

Section: Ief Of Serum Transferrin (Tf-ief)mentioning

confidence: 99%

Two Argentinean Siblings with CDG-Ix: A Novel Type of Congenital Disorder of Glycosylation?

et al. 2011

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Congenital disorders of glycosylation (CDG) are genetic diseases caused by abnormal protein and lipid glycosylation. In this chapter, we report the clinical, biochemical, and molecular findings in two siblings with an unidentified CDG (CDG-Ix). They are the first and the third child of healthy consanguineous Argentinean parents. Patient 1 is now a 11-year-old girl, and patient 2 died at the age of 4 months. Their clinical picture involved liver dysfunction in the neonatal period, psychomotor retardation, microcephaly, seizures, axial hypotonia, feeding difficulties, and hepatomegaly. Patient 1 also developed strabismus and cataract. They showed a type 1 pattern of serum sialotransferrin. Enzymatic analysis for phosphomannomutase and phosphomannose isomerase in leukocytes and fibroblasts excluded PMM2-CDG and MPI-CDG. Lipid-linked oligosaccharide (LLO) analysis showed a normal profile. Therefore, this result could point to a deficiency in the dolichol metabolism. In this context, ALG8-CDG, DPAGT1-CDG, and SRD5A3-CDG were analyzed and no defects were identified. In conclusion, we could not identify the genetic deficiency in these patients yet. Further studies are underway to identify the basic defect in them, taking into account the new CDG types that have been recently described.

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Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome

Cited by 260 publications

References 4 publications

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Two Argentinean Siblings with CDG-Ix: A Novel Type of Congenital Disorder of Glycosylation?

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