TRAPPC11 – Triple A Syndrome

Triple A syndrome (Allgrove syndrome) is a rare autosomal recessive disorder characterized by ACTH-resistant adrenal insufficiency, achalasia, and alacrimia. While AAAS mutations explain most cases, approximately 30% of patients remain genetically unresolved. Early linkage studies mapped the triple A locus to chromosome 12q13 in North African and Mediterranean families, indicating a single founder haplotype (PMID:10951524).

In 2017, whole-exome sequencing in two unrelated Turkish families negative for AAAS variants identified a homozygous splice-site mutation in TRAPPC11, c.1893+3A>G, in 4 probands from 2 families with triple A–like features including achalasia (HP:0002571), alacrima (HP:0000522), and myopathy (HP:0003198) (PMID:27707803). This variant causes incomplete exon skipping, reduced full-length mRNA and protein levels, hypoglycosylation of LAMP1, and delayed Golgi trafficking in patient fibroblasts, confirming a pathogenic role concordant with human phenotype.

Key take-home: TRAPPC11 should be included in genetic testing panels for Triple A Syndrome in AAAS-negative patients to improve diagnostic yield and guide management.

References

• European journal of human genetics | 2000 | Linkage disequilibrium in inbred North African families allows fine genetic and physical mapping of triple A syndrome. PMID:10951524
• Journal of medical genetics | 2017 | A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima. PMID:27707803

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