Dataset Information

Mutation of TBCK causes a rare recessive developmental disorder.

ABSTRACT:

Objective

To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.

Methods

Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. Inspection of genetic variability within this region led to the identification of a novel mutation. Sanger sequencing confirmed segregation of the mutation with disease.

Results

All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del).

Conclusions

This finding provides the genetic cause of a severe inherited disease in a family and extends the number of mutations and phenotypes associated with this recently identified disease gene.

SUBMITTER: Guerreiro RJ

PROVIDER: S-EPMC4881620 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Mutation of TBCK causes a rare recessive developmental disorder.

Guerreiro Rita J RJ Brown Rachel R Dian Donnai D de Goede Christian C Bras Jose J Mole Sara E SE

Neurology. Genetics 20160524 3

<h4>Objective</h4>To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.<h4>Methods</h4>Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. ...[more]

PMID: 27275012

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Project description:OBJECTIVE:Autosomal-recessive mutations in TBCK cause intellectual disability of variable severity. Although the physiological function of TBCK remains unclear, loss-of-function mutations are associated with inhibition of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Given that mTORC1 signaling is known to regulate autophagy, we hypothesized that TBCK-encephalopathy patients with a neurodegenerative course have defects in autophagic-lysosomal dysfunction. METHODS:Children (n?=?8) of Puerto Rican (Boricua) descent affected with homozygous TBCK p.R126X mutations underwent extensive neurological phenotyping and neurophysiological studies. We quantified autophagosome content in TBCK-/- patient-derived fibroblasts by immunostaining and assayed autophagic markers by western assay. Free sialylated oligosaccharide profiles were assayed in patient's urine and fibroblasts. RESULTS:The neurological phenotype of children with TBCK p.R126X mutations, which we call TBCK-encephaloneuronopathy (TBCKE), include congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy, and epilepsy. Systemic features include coarse facies, dyslipidemia, and osteoporosis. TBCK-/- fibroblasts in vitro exhibit increased numbers of LC3+ autophagosomes and increased autophagic flux by immunoblots. Free oligosaccharide profiles in fibroblasts and urine of TBCKE patients differ from control fibroblasts and are ameliorated by treatment with the mTORC1 activator leucine. INTERPRETATION:TBCKE is a clinically distinguishable syndrome with progressive central and peripheral nervous system dysfunction, consistently observed in patients with the p.R126X mutation. We provide evidence that inappropriate autophagy in the absence of cellular stressors may play a role in this disorder, and that mTORC1 activation may ameliorate the autophagic-lysosomal system dysfunction. Free oligosaccharide profiles could serve as a novel biomarker for this disorder as well as a tool to evaluate potential therapeutic interventions. Ann Neurol 2018;83:153-165.

Dataset Information

Mutation of TBCK causes a rare recessive developmental disorder.

Objective

Methods

Results

Conclusions

Publications

Mutation of TBCK causes a rare recessive developmental disorder.

Similar Datasets

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