Background Triple A syndrome (MIM #231550) is associated with mutations in the AAAS gene. However, about 30% of patients with triple A syndrome symptoms but an unresolved diagnosis do not harbour mutations in AAAS.
Objective Search for novel genetic defects in families with a triple A-like phenotype in whom AAAS mutations are not detected.
Methods Genome-wide linkage analysis, whole-exome sequencing and functional analyses were used to discover and verify a novel genetic defect in two families with achalasia, alacrima, myopathy and further symptoms. Effect and pathogenicity of the mutation were verified by cell biological studies.
Results We identified a homozygous splice mutation in TRAPPC11 (c.1893+3A>G, [NM_021942.5], g.4:184,607,904A>G [hg19]) in four patients from two unrelated families leading to incomplete exon skipping and reduction in full-length mRNA levels. TRAPPC11 encodes for trafficking protein particle complex subunit 11 (TRAPPC11), a protein of the transport protein particle (TRAPP) complex. Western blot analysis revealed a dramatic decrease in full-length TRAPPC11 protein levels and hypoglycosylation of LAMP1. Trafficking experiments in patient fibroblasts revealed a delayed arrival of marker proteins in the Golgi and a delay in their release from the Golgi to the plasma membrane. Mutations in TRAPPC11 have previously been described to cause limb-girdle muscular dystrophy type 2S (MIM #615356). Indeed, muscle histology of our patients also revealed mild dystrophic changes. Immunohistochemically, β-sarcoglycan was absent from focal patches.
Conclusions The identified novel TRAPPC11 mutation represents an expansion of the myopathy phenotype described before and is characterised particularly by achalasia, alacrima, neurological and muscular phenotypes.
- Triple A syndrome
- Transport protein particle complex
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KK, MPM and KP contributed equally.
Contributors EU and FH phenotyped the patients. MSch and KK processed, analysed and validated the whole exome sequencing data. SK, DL and FR performed the Sanger sequencing. DL performed RNA and microsatellite analysis. MPM and KP performed western blotting, VSVG–GFP ts045 assay, fluorescence and time-lapse microscopy. GD performed the immunohistochemistry. KK, MPM, KP, RJ and MSa analysed and interpreted the data. AH, MSa and KK supervised the work and obtained funding support. KK and MSa wrote the manuscript. All authors read the final version of the manuscript and gave their permission for publication.
Funding This work was supported by a DFG grant HU 895/5-1 and HU 895/5-2 (Clinical Research Unit 252) to AH, SFB 665 TP C4 to MSch, a Canadian Institutes for Health Research grant and a Natural Sciences and Engineering Research Council grant to MSa.
Competing interests None declared.
Patient consent Parental consent obtained.
Ethics approval Local ethics review board (Medical Faculty, Technical University Dresden; EK820897).
Provenance and peer review Not commissioned; externally peer reviewed.