Abstract
TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. Variants in TRAPPC11 have been reported to be associated with a broad spectrum of phenotypes but all affected individuals display muscular pathology. Identifying additional variants will further our understanding of the clinical spectrum of phenotypes and will reveal regions of the protein critical for its functions. Here we report three individuals from unrelated families that have bi-allellic TRAPPC11 variants. Subject 1 harbors a compound heterozygous variant (c.1287 + 5G > A and c.3379_3380insT). The former variant results in a partial deletion of the foie gras domain (p.Ala372_Ser429del), while the latter variant results in a frame-shift and extension at the carboxy terminus (p.Asp1127Valfs*47). Subjects 2 and 3 both harbour a homozygous missense variant (c.2938G > A; p.Gly980Arg). Fibroblasts from all three subjects displayed membrane trafficking defects manifested as delayed endoplasmic reticulum (ER)-to-Golgi transport and/or a delay in protein exit from the Golgi. All three individuals also show a defect in glycosylation of an ER-resident glycoprotein. However, only the compound heterozygous subject displayed an autophagic flux defect. Collectively, our characterization of these individuals with bi-allelic TRAPPC11 variants highlights the functional importance of the carboxy-terminal portion of the protein.
Highlights
TRAPPC11 was identified as a component of the transport protein particle (TRAPP) III complex that functions in membrane trafficking and autophagy
Muscle biopsy was performed at the age of 4 years and showed minimal myopathic changes consisting of mild variation in muscle fibre diameter, a population of fibres with weak cytochrome c activity and a few fibres of normal size positive for neonatal myosin indicating fiber regeneration (Fig. 1b)
It is becoming increasingly clear that proteins described as TRAPP subunits and thought to be stable components of a mammalian TRAPP complex, may not be stably associated with the complex
Summary
TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. The TRAPPC11 protein was identified as a component that associates with TRAPP III1,2. This complex was originally reported to play an as yet undefined role in membrane trafficking in the biosynthetic pathway. S4 c.1287 + 5G > A not reported, family history of early onset none walks without support not performed 700–1000 no no generalized ataxia, primary generalized seizures moderate no mild cerebral atrophy no no component of this complex, functions prior to autophagosome-lysosome fusion[6]. Elucidating the roles of TRAPP III proteins both within and outside of the complex is important to better understand their cellular functions. In the case of TRAPPC11 and other TRAPP proteins, it is possible that regions or domains of the protein may play a role in different cellular pathways
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