Carbohydrate-deficient Glycoprotein Syndrome Type II. An Autosomal Recessive N-acetylglucosaminyltransferase II Deficiency Different from Typical Hereditary Erythroblastic Multinuclearity, with a Positive Acidified-serum Lysis Test (HEMPAS)

Abstract

EJB 95 0392/5Carbohydrate-deficient glycoprotein syndromes (CDGS) are a family of multisystemic congenital diseases resulting in underglycosylated glycoproteins, suggesting defective N-glycan assembly. Fibroblast extracts from two patients with a recently described variant of this disease (CDGS type 11) have previously been shown to have over 98 % reduced activity of UDP-GlcNAc :a-6-~-mannoside /?-1,2-N-acetylglucosaminyltransferase I1 [GlcNAc-TIT; Jaeken, J., Schachter, H., Carchon, H., De Cock, P., Coddeville, B. & Spik, G. (1994) Arch. Dis. Childhood 71,123-1271. We show in this paper that mononuclear cell extracts from one of these CDGS type-I1 patients have no detectable GlcNAc-TI1 activity and that similar extracts from 12 blood relatives of the patient, including his father, mother and brother, have GlcNAc-TI1 levels 32-67% that of normal levels (average 50.1 % 2 10.7% SD), consistent with an autosomal recessive disease. The poly(N-acetyllactosamine) content of erythrocyte membrane glycoproteins bands 3 and 4.5 of this CDGS patient were estimated, by tomato lectin blotting, to be reduced by 50% relative to samples obtained from blood relatives and normal controls. Similar to patients with hereditary erythroblastic multinuclearity with a positive acidified-serum lysis test (HEMPAS), erythrocyte membrane glycoproteins in the CDGS patient have increased reactivities with concanavalin A, demonstrating the presence of hybrid or oligomannose carbohydrate structures. However, bands 3 and 4.5 in HEMPAS erythrocytes have almost complete lack of poly(N-acetyllactosaine). Furthermore, CDGS type-I1 patients have a totally different clinical presentation and their erythrocytes do not show the serology typical of HEMPAS, suggesting that the genetic lesions responsible for these two diseases are possibly different.

Expression of Three Caenorhabditis elegans N-Acetylglucosaminyltransferase I Genes during Development

“…In contrast to the mammalian GnT I genes in which the entire open reading frame is on a single exon, the gly-12, gly-13, and gly-14 genes have multiple exons (14,12, and 12, respectively). However, although the identity between the C. elegans and mammalian GnT I amino acid sequences is less than 50%, the GLY-12 and GLY-14 enzymes show kinetic parameters very similar to the rabbit enzyme.…”

“…Another variant of CDGS type 1 has been described recently with a defect in the phosphomannose isomerase gene (10). Two children with CDGS type 2 have inactivating point mutations in the GnT II gene (11)(12)(13). Several other congenital diseases are associated with defective complex N-glycan synthesis (14).…”

Abnormal Glycosylation of Red Cell Membrane Band 3 in the Congenital Disorder of Glycosylation Ig

“…Apart from this study, glycosylation abnormalities of band 3 were reported only in CDG Ia (9) and CDG IIa (8). No hematological signs were recorded.…”

“…It is odd that there were no gross hematological signs among so many manifestations and despite pronounced alterations of the band 3 glycan moiety. Previously, aberrant glycosylation of band 3 was described in one patient with a CDG II (8), and abnormalities of both band 3 and glycophorin A were reported in three patients with CDG Ia (9).…”

The congenital disorders of glycosylation: A multifaceted group of syndromes

“…Today there are 12 known CDG Types I 10 -22 and 6 Types II. [23][24][25][26][27][28] Clinically, many symptoms are shared by several CDG subtypes-psychomotor retardation, ataxia, failure to thrive, dysmorphic features (including inverted nipples and subcutaneous fat pads), and coagulopathies-but there are also noticeable differences. Below follows a short description of each individual subtype.…”