Recessive TRAPPC11 Mutations Cause a Disease Spectrum of Limb Girdle Muscular Dystrophy and Myopathy with Movement Disorder and Intellectual Disability

Abstract

Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.

A novelTRAPPC11mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima

“…Disturbances in these processes can have dramatic effects on cell metabolism. In contrast to our observation of LAMP1 hypoglycosylation, a previous study describing another TRAPPC11 mutation demonstrated not only a reduction in the cellular levels of LAMP1 and LAMP2, but the proteins were observed in a higher molecular size region of the gel as compared with controls, suggesting that they might have a higher degree of glycosylation 26. Taken together with these previous studies, our data suggest that the type of mutation, and not necessarily the cellular levels of TRAPPC11, can influence protein glycosylation.…”

“…Small amounts of full-length TRAPPC11 in the lysates from the affected individuals are consistent with the incomplete splicing defect and reduced mRNA levels of the regular splice product described above. In a previous study characterising the TRAPPC11 mutations p.G980R and p.A372_S429del, hyperglycosylation of lysosomal-associated membrane protein 1 (LAMP1) was demonstrated 26. In contrast to that study, we found that LAMP1 was hypoglycosylated in both F1.II:1 and F1.II:2 (figure 3A).…”

“…A second homozygous mutation in which a small portion of the protein is deleted resulted in myopathy, ataxia, hyperkinetic movements and intellectual disability 26. Furthermore, one Asian patient carrying a compound heterozygous mutation in TRAPPC11 was described with congenital muscular dystrophy (CMD), progressive fatty liver and infantile-onset cataract 35.…”

Clinical massively parallel sequencing for the diagnosis of myopathies

“…Exome and genome sequencing has revolutionized this mutation discovery process by allowing rapid identification of the homozygous nucleotide change present in all affected family members. Mutations in seven genes, MEGF10, ISPD, KLHL40, TRAPPC11, HACD1, KLHL41, MICU1, were identified using this approach (see Table 3 for muscle disorders caused by mutations in these genes) [15,21,[24][25][26][27][28]. In several cases of dominant myopathies, the list of candidate genes was narrowed down using genome-wide linkage analysis and subjected to massively parallel sequencing.…”

A homozygous founder mutation inTRAPPC6Bassociates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features

“…There are three TRAPP complexes that share a core of seven subunits and contain additional subunits that give their specific functions (figure 1A): 1) TRAPP I regulates vesicle trafficking from the ER to early Golgi; 2) TRAPP II controls intra-Golgi trafficking and 3) TRAPP III is required for autophagy 1. Mutations in TRAPP subunits have been associated with several human diseases, ranging from spondyloepiphyseal dysplasia tarda (TrappC2 (MIM 300202); adaptor),2 limb girdle muscular dystrophy (TrappC11 (MIM 614138); TRAPP III)3 and intellectual disability with microcephaly (TrappC9 (MIM 611966); TRAPP II) 4. However, how mutations in different TRAPP subunits lead to such diverse clinical phenotypes remains unclear.…”