Congenital muscular dystrophy with fatty liver and infantile-onset cataract caused by TRAPPC11 mutations: broadening of the phenotype
- Wen-Chen Liang†1, 3,
- Wenhua Zhu†5, 6, 7,
- Satomi Mitsuhashi5, 6Email author,
- Satoru Noguchi5, 6,
- Michael Sacher8, 9,
- Megumu Ogawa5,
- Hsiang-Hung Shih1, 3,
- Yuh-Jyh Jong1, 2, 4, 10 and
- Ichizo Nishino5, 6
© Liang et al. 2015
Received: 10 July 2015
Accepted: 7 August 2015
Published: 28 August 2015
Transport protein particle (TRAPP) is a multiprotein complex involved in endoplasmic reticulum-to-Golgi trafficking. Zebrafish with a mutation in the TRAPPC11 orthologue showed hepatomegaly with steatosis and defects in visual system development. In humans, TRAPPC11 mutations have been reported in only three families showing limb-girdle muscular dystrophy (LGMD) or myopathy with movement disorders and intellectual disability.
We screened muscular dystrophy genes using next-generation sequencing and performed associated molecular and biochemical analyses in a patient with fatty liver and cataract in addition to infantile-onset muscle weakness.
We identified the first Asian patient with TRAPPC11 mutations. Muscle pathology demonstrated typical dystrophic changes and liver biopsy revealed steatosis. The patient carried compound heterozygous mutations of a previously reported missense and a novel splice-site mutation. The splice-site change produced two aberrantly-spliced transcripts that were both predicted to result in translational frameshift and truncated proteins. Full-length TRAPPC11 protein was undetectable on immunoblotting.
This report widens the phenotype of TRAPPC11-opathy as the patient showed the following: (1) congenital muscular dystrophy phenotype rather than LGMD; (2) steatosis and infantile-onset cataract, both not observed in previously reported patients; but (3) no ataxia or abnormal movement, clearly indicating that TRAPPC11 plays a physiological role in multiple tissues in human.
KeywordsTransport protein particle (TRAPP) Endoplasmic reticulum-to-Golgi trafficking Steatosis Cataract Congenital muscular dystrophy
Transport protein particle (TRAPP) is a multiprotein complex involved in endoplasmic reticulum (ER)-to-Golgi trafficking and possibly other membrane trafficking steps [1, 2]. Oligomerization of TRAPP can give rise to complexes with variable components in any one of several positions and might allow for a combinatorial diversification of TRAPP function, perhaps regulating cell-specific activities . A loss-of-function mutation in the zebrafish TRAPPC11 orthologue is characterized by hepatomegaly with steatosis, thereby named foie gras mutant, and by defects in visual system development [4, 5]. In human, there has been only one report of TRAPPC11 mutations, describing one Syrian family with limb-girdle muscular dystrophy (LGMD) phenotype, which was labeled LGMD2S, and two families of Hutterite ancestry with myopathy phenotype, movement disorders and intellectual disability . In addition to impaired TRAPP assembly and disrupted Golgi apparatus architecture, alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 were also observed in the cells of affected individuals, suggesting a defect in the transport of secretory proteins as the underlying pathomechanism. We herein report the first Asian patient carrying compound heterozygous mutations in the TRAPPC11 gene who developed congenital muscular dystrophy (CMD) phenotype with prominent fatty liver and infantile-onset cataract, further broadening the clinical phenotype of TRAPPC11-opathy.
Clinical and pathological features
Molecular and protein analyses
We have demonstrated that the novel splice-site mutation c.661-1G > T results in two different aberrant transcripts, predicted to produce two truncated proteins. The absence of a full-length TRAPPC11 protein by Western blot analysis suggests the possibility that Gly980Arg mutation may destabilize the protein, which was also shown in the previous report describing Gly980Arg in a homozygous manner, or may enhance its degradation .
Comparison of the present patient and previously reported patients with TRAPPC11 mutations
c.2938G > A homoa
c.1287 + 5G > A homoa
c.2938G > A/c.661-1G > T
Number of patient
Age of onset
Early school age
Early childhood onset
Around 1-year-old or even earlier
Proximal weakness, myalgia, cramps
Mild weakness and hypotonia (2)b
Proximal weakness, hypotonia
Within normal limit
<3rd percentile (4)b
Other neurological problems
Generalized seizure (1)b
abnormal EEG (2)b
Mild cerebral atrophy (2)b
Reduced white matter volume
Enlarged right ventricle (1)b
Hip dysplasia, scoliosis
Limb asymmetry (1)b
Esotropia and myopia (1)b cataract (1)b
Exophoria, anisometropia, and amblyopia (1)b
It is noteworthy that, although the patient presented here did not have microcephaly, abnormal involuntary movements, nor cerebral atrophy, which were previously reported in the patients with TRAPPC11 mutations , her brain MRI at the age of 3 years and 6 months revealed slightly reduced white matter volume. Reduced white matter volume in pediatric patients is usually associated with periventricular leukomalacia, the major substrate of neurologic deficits in premature infants . However, it might also be the consequence of diffuse axonal damage or maldevelopment such as hypomyelination, which may not be easily differentiated by imaging without serial studies [9, 10]. Regarding the normal maternal pregnancy and birth history of the patient in this study, ischemic/hypoxic injury-causing white matter volume loss seems unlikely. As the T1- and T2-weighted images did not show notably abnormal intensity, mild hypomyelination was thus considered. Interestingly, the deficiency of a Golgi-associated protein, dymeclin, was recently reported to cause postnatal microcephaly, hypomelination, and ER-to-Golgi trafficking defects in both mice and humans . Although dymeclin has not yet known to be a binding partner of TRAPP complex, the similar Golgi-associated nature and clinical phenotype are indicative of probable interaction and common pathomechanism of these two proteins. The present study also provides further supportive evidence of the relationship between the impaired cellular trafficking and brain phenotype in TRAPPC11-associated disease.
Collectively, this study widens the phenotype of TRAPPC11-opathy. Although the detailed mechanism causing intracellular lipid storage in liver is still unknown, the phenotype of the patient in this study clearly indicates that TRAPPC11 plays a physiological role in multiple tissues in humans including the liver, muscle, eye, brain, and bone. This may be due to impairment of TRAPPC11 functions in multiple membrane-trafficking pathways or other processes.
Written informed consent was obtained from the patient’s mother for publication of this Case Report and any accompanying images. A copy of the written consent is available to Editors of this journal on request.
transport protein particle
limb-girdle muscular dystrophy
lysosome-associated membrane protein
congenital muscular dystrophy
This study was supported partly by Intramural Research Grant (26-7, 26-8) for Neurological and Psychiatric Disorders of NCNP, Health and Labour Sciences Research Grants for Comprehensive Research on Persons with Disabilities (H25-Shinkei Kin-Ippan-004) and Practical Research Project for Rare/Intractable Diseases (H26-Itaku (Nan)-Ippan-081) from Japan Agency for Medical Research and Development, AMED. WZ is supported by the State Scholarship Fund from China Scholarship Council (CSC_201406105045). MS is supported by the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Canada Foundation for Innovation, and is a member of the Groupe de Recherche Axé sur la Structure des Protéines (GRASP) network.
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