Guerreiro RJ, Brown R, Dian D, de Goede C, Bras J, Mole SE. Mutation of TBCK
causes a rare recessive developmental disorder. Neurol Genet. 2016 May
To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.
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.
All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del).
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.
From the article:
Because both parents are healthy and 3 of 4 children, of both sexes, were affected, we assumed a recessive mode of inheritance. Whole-genome genotyping identified a single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553–108,609,628) that was shared by both affected siblings but was absent from the unaffected (tables e-1 and e-2, figure e-1 at Neurology.org/ng). Inspection of the whole-exome data for genetic variability within this region led to the identification of a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del). Sanger sequencing confirmed segregation of the mutation with disease. The only tissue available was a lymphocyte cell line from II-3. However, quantitative PCR analysis revealed no significant differences in transcript levels.
A splicing mutation in TBCK, discovered during a large-scale WES project in consanguineous families, has been recently reported. The clinical symptoms in the patient described previously and the patients described here are remarkably similar and include global developmental delay, epilepsy, dysmorphism, and hypotonia. However, the first patient also displayed ventricular septal defects and did not have precocious puberty. The family described here is not known to be consanguineous…
TBCK is a poorly characterized protein and currently has no assigned function, although it is reported to be a putative Rab GTPase activating protein. Recent work has suggested that TBCK may have a role in epidermal growth factor signaling, endocytosis, and cell migration. Others have shown that TBCK knockdown suppresses mechanistic target of rapamycin (mTOR) signaling and inhibits cell proliferation. Conversely, others have reported that TBCK activity inhibits cell proliferation.8 The paucity of articles directly investigating TBCK function, and the conflicting evidence put forward by those that have, reveals the need for further work to define the function of TBCK in the context of specific cell types, and the potentially different roles for alternative isoforms. The deletion mutation reported here falls within exon 11 and creates a premature stop codon. Clearly, more extensive functional assays are needed to understand the role of TBCK and the downstream effects of the mutations so far identified.
The data presented herein and previously3 strongly argue for the role of TBCK in this novel syndrome.