KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further... Show moreKPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models.Kptn−/− mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants.Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1.By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity. Show less
Breast cancer risk is approximately twice as high in first-degree relatives of female breast cancer cases than in women in the general population. Less than half of this risk can be attributed to... Show moreBreast cancer risk is approximately twice as high in first-degree relatives of female breast cancer cases than in women in the general population. Less than half of this risk can be attributed to the currently known genetic risk factors. Recessive risk alleles represent a relatively underexplored explanation for the remainder of familial risk. To address this, we selected 19 non-BRCA1/2 breast cancer families in which at least three siblings were affected, while no first-degree relatives of the previous or following generation had breast cancer. Germline DNA from one of the siblings was subjected to exome sequencing, while all affected siblings were genotyped using SNP arrays to assess haplotype sharing and to calculate a polygenic risk score (PRS) based on 160 low-risk variants. We found no convincing candidate recessive alleles among exome sequencing variants in genomic regions for which all three siblings shared two haplotypes. However, we found two families in which all affected siblings carried the CHEK2*1100delC. In addition, the average normalized PRS of the "recessive" family probands (0.81) was significantly higher than that in both general population cases (0.35, P = .026) and controls (P = .0004). These findings suggest that the familial aggregation is, at least in part, explained by a polygenic effect of common low-risk variants and rarer intermediate-risk variants, while we did not find evidence of a role for novel recessive risk alleles. Show less
Hofmann, K.; Zweier, M.; Sticht, H.; Zweier, C.; Wittmann, W.; Hoyer, J.; ... ; Rauch, A. 2013
