A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism

Abstract

Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5α-reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5α-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism.

Novel genetic causes for cerebral visual impairment

“…Previously, CVI has been reported as part of congenital disorders of glycosylation (CDG) type 1a (PMM2), type 1q (SRD5A3), and type 1v (NGLY1). 8,28,30,31 The phenotype of patient 2 with NGLY1 variants is similar to the previously reported patients, including the microcephaly, hypotonia, movement disorder, and alacrima. 28,32,33 Variants in SLC35A2 lead to CDG type 2m, featured by ID, epilepsy, facial dysmorphisms, and transient abnormalities in transferin testing.…”

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

“…Their conclusions were based foremost on mutations in SRD5A3 in a large Emirati family from Baluchi (Southern Iran) and children from seven other families. Subsequently, other studies also identified mutations in patients further supporting SRD5A3 as associated with CDGs (Gründahl et al, 2012;Kahrizi et al, 2011;Kasapkara et al, 2012;Morava et al, 2010). Interestingly, these patients exhibited residual dolichol levels, implying that there must be an alternative pathway for dolichol biosynthesis Gründahl et al, 2012).…”

5α-Reduced glucocorticoids: a story of natural selection

“…Although the presence of multiple enzymes was initially suggested , Godoy et al 2011, genes encoding two isozymes (SRD5A1 and SRD5A2) were later cloned in the 1990s (Andersson & Russell 1990, Andersson et al 1991. SRD5A1 and SRD5A2 are members of a larger family of genes containing 5a-reductase domains, the other members being encoded by the genes SRD5A3 and GPSN2-SRD5A2L2, whose roles remain less clear, but may involve reduction of non-steroidal substrates (Cantagrel et al 2010). SRD5A3 was identified through expression profiling of hormone refractory prostate cancer cells and its transcript is expressed in higher levels in malignancy in comparison with benign tissues (Uemura et al 2008, Yamana et al 2010, Godoy et al 2011.…”

“…To date, similar catalytic activities have not been demonstrated for GCs. However, a distinct role for this enzyme has been proposed to catalyse conversion of polyprenol to dolichol and mutations in SRD5A3 give rise to a congenital disorder of glycosylation (Cantagrel et al 2010, Morava et al 2010, Kahrizi et al 2011.…”