We present a comprehensive spectrum of mutations of GP1BA (GPIbα), GP1BB (GPIbβ) and GP9 (GPIX) causing Bernard-Soulier syndrome (BSS), a rare bleeding autosomal recessive disorder. Of the 211 families enrolled, 28% have mutations in GP1BA, another 28% in GP1BB and the remaining 44% in GP9. Excluding a few founder effects, most of the 112 different mutations identified are private. Missense variants, whose pathogenetic role should be determined through functional studies, accounts for more than half BSS alleles.

The 364 exon TTN gene encodes the giant protein titin, a key player in cardiac and skeletal muscles. Lately, NGS is revealing TTN as a major gene in human inherited disease, with 127 TTN disease-causing mutations reported in patients with at least 10 different conditions. Here we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern and phenotype-genotype correlations, alongside with their implications for basic research and human health.

Screenshot of the home page of GALT Protein Database 2.0, with the link to full access and description of its features. In this database we not only collect a list of the known missense variations for GALT enzyme, but in addition, we provide information about their effect on GALT structure and possibly, function, obtained by modeling and analyzing the structures of the missense variants.

The p.Arg116His mutation in the DNA binding domain of the heat shock transcription factor HSF4, reported to be associated with age-related cataracts in humans recapitulates the most prevalent childhood lamellar cataract phenotype (arrow), when introduced into mice via bacterial artificial chromosome transgenesis. This data suggests that the presence of this mutation in ‘normal’ individuals does not impair the visual function. Slit lamp images of age matched (21 days old) wild-type (WT, left) and F2 transgenic mouse lens (right) are shown.

We adopted an evolution-guided functional approach to identify potential genetic determinants of TRIM22 function. We showed that positive selection is operating on multiple residues that cluster in putative functional regions and are predicted to be functionally damaging. Our data characterize the extensive genetic variation in TRIM22 and identify rs1063303:G>C as a highly prevalent SNP that influences its function.

Corneal stroma accumulates water osmotically, which is countered by the “pumping” function of endothelial cells. SLC4A11 forms a water conductive pathway, whose mutations lead to blinding corneal edema. Most SLC4A11 mutants (red x) are retained in the endoplasmic reticulum, but this work found: SLC4A11 mutants could be rescued to the cell surface and are functional once rescued, providing hope for therapeutic strategies aimed at rescuing diseased SLC411 to the cell surface.

This study demonstrates that Marshall-Smith syndrome is consistently caused by de novo NFIX mutations. It is presented for the first time that exon deletions including a recurrent AluY-mediated exon 6 and 7 deletion account for roughly a quarter of cases. MSS-associated mutations lead to mutant proteins with intact DNA-binding and dimerization domains(DNAbd, MH1), while they have various alterations of their transcriptional transactivation/repression domains (CTF/NFI). Thereby they are presumed to exert dominant negative effects.

We report two new putative TOR1A mutations (p.A14_P15del and p.E121K) that we examined functionally in comparison with wildtype protein. Our findings demonstrate functional changes on different levels.Western blot analysis of cross-linking experiments with formaldehyde (FA) and quantification of TOR1A levels in SH-SY5Y cells expressing TOR1A show significantly enhanced dimerization at 74 kDa for p.A14_P15del mutant TOR1A (NT: non-treated).

The notable effect of reduced mismatch repair gene expression on the repair efficiency provides a preliminary indication of the relative expression levelss required for wild-type function. These findings suggest that the in vitro MMR assay could be used to recognize expression levels indicative of Lynch syndrome.

The most common cause of cerebral creatine syndromes is caused by mutations in the creatine transporter (SLC6A8), and no effective treatment is available yet. We performed RNA sequencing to investigate the molecular pathophysiology of this disorder, using fibroblast cells derived from eight unrelated individuals with SLC6A8 deficiency. Especially the expression of genes encoding components of the extracellular matrix and cytoskeleton altered due to SLC6A8 deficiency, and suggests an important role for creatine in the structural development and maintenance of cells.

Uterine leiomyomas are the most common human tumors with highly specific mutations reported in MED12 exon 2. Here, we show that mutations occur recurrently also in MED12 exon 1. Transcriptome-wide gene expression profiling and functional analyses show that exon 1 and 2 mutations promote tumorigenesis through similar mechanism. These results bring new knowledge on MED12 function and highlight the role of MED12 in human tumorigenesis.

A. SPOP is one of the most frequently affected genes bysomatic point mutations in prostate cancer.

B. SPOP recognizes aSer/Thr-rich degron in the transactivation domain of DDIT3 andtriggers DDIT3 degradation via the ubiquitin-proteasome pathway.

C. Prostate cancer-associated mutants of SPOP aredefective in promoting DDIT3 degradation.