A case of fatal Type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity.

BACKGROUND: Type I congenital disorders of glycosylation (CDG-I) are mostly complex multisystemic diseases associated with hypoglycosylated serum glycoproteins. A subgroup harbour mutations in genes necessary for the biosynthesis of the dolichol-linked oligosaccharide (DLO) precursor that is essential for protein N-glycosylation. Here, our objective was to identify the molecular origins of disease in such a CDG-Ix patient presenting with axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, cryptorchidism and sensorineural deafness associated with hypo glycosylated serum glycoproteins. RESULTS: Targeted sequencing of DNA revealed a splice site mutation in intron 5 and a non-sense mutation in exon 4 of the dehydrodolichol diphosphate synthase gene (DHDDS). Skin biopsy fibroblasts derived from the patient revealed ~20 % residual DHDDS mRNA, ~35 % residual DHDDS activity, reduced dolichol-phosphate, truncated DLO and N-glycans, and an increased ratio of [2-(3)H]mannose labeled glycoprotein to [2-(3)H]mannose labeled DLO. Predicted truncated DHDDS transcripts did not complement rer2-deficient yeast. SiRNA-mediated down-regulation of DHDDS in human hepatocellular carcinoma HepG2 cells largely mirrored the biochemical phenotype of cells from the patient. The patient also harboured the homozygous ALG6(F304S) variant, which does not cause CDG but has been reported to be more frequent in PMM2-CDG patients with severe/fatal disease than in those with moderate presentations. WES did not reveal other strong candidate causal genes. CONCLUSIONS: We describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition.

A monoclonal antibody to the Hodgkin's disease-associated antigen CD30 induces activation and long-term growth of human autoreactive gamma delta T cell clone.

In order to identify cell surface structures involved in the activation and growth of human-cloned T lymphocytes, we developed monoclonal antibodies against an autoreactive TcR gamma delta-bearing clone termed DS6. Antibodies were screened for their agonistic properties with the immunizing T cell clone. In the present report, we describe a CD30 mAb, termed BY88, that was capable of inducing, in a short-term assay, a strong proliferation of the T cell clone DS6 when added in combination with IL2 or phorbol myristate acetate. More important was the finding that in the total absence of feeder cells, BY88 mAb and recombinant IL2 were capable of maintaining long-term growth of DS6 cells. As this finding could not be extended to alloreactive cloned T lymphocytes, it is suggested that activation of T lymphocytes through the CD30 molecule is restricted to a T cell subset including autoreactive TCR gamma delta-bearing lymphocytes.