Severe infantile acute encephalopathy and COG4 mutation: CDG IIJ

Rucián, Ana Felipe; Ruiz, Alfons Macaya; Riera, M. del Toro; Girós, M.

doi:10.1016/j.ejpn.2017.04.1052

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“…We show that a heterozygous de novo p.Gly516Arg COG4 variant is responsible for SWS, a rare skeletal dysplasia characterized by short stature, facial dysmorphisms, hearing loss, cataracts, developmental delay, and normal cognition. This is phenotypically distinct from the three reported individuals with classic, biallelic loss-of-function, or hypomorphic COG4 mutations, who presented with seizures, hypotonia, intellectual disability, microcephaly, elevated transaminases, and, in one case, recurrent infections, 26,[32][33][34] and from individuals with loss-of-function mutations in other COG subunits associated with congenital disorders of glycosylation (CDG). These distinct phenotypes and the recurrent nature of the p.Gly516Arg variant therefore suggest the SWS mutation to be gainof-function.…”

Section: Discussionmentioning

confidence: 56%

A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation

Ferreira

Xia

Clément

et al. 2018

The American Journal of Human Genetics

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The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

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Section: Discussionmentioning

confidence: 56%