Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Hum Mutat [journal]
- Functional Studies of Tyrosine Hydroxylase Missense Variants Reveal Distinct Patterns of Molecular Defects in DOPA Responsive Dystonia. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 21.
Congenital tyrosine hydroxylase deficiency (THD) is found in autosomal recessive DOPA responsive dystonia and related neurological syndromes. The clinical manifestations of THD are variable, ranging from early onset lethal disease to mild Parkinson disease-like symptoms appearing in adolescence. Until 2014, approximately 70 THD patients with a total of 40 different disease related missense mutations, 5 nonsense mutations and 3 mutations in the promoter region of the TH gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of TH variants previously not studied (N = 23). We compared the in vitro solubility, thermal stability and kinetic properties of the TH variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some TH variants had specific kinetic anomalies and phenylalanine hydroxylase and DOPA oxidase activities were measured for variants that showed signs of altered substrate binding. p.Arg233His, p.Gly247Ser and p.Phe375Leu had shifted substrate specificity from tyrosine to phenylalanine and DOPA, while p.Cys359Phe had an impaired activity towards these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for THD patients. This article is protected by copyright. All rights reserved.
- Performance of Protein Disorder Prediction Programs on Amino Acid Substitutions. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 21.
Many proteins contain intrinsically disordered regions, which may be crucial for function, but on the other hand be related to the pathogenicity of variants. Prediction programs have been developed to detect disordered regions from sequences and used to predict the consequences of variants, although, their performance for this task has not been assessed. We tested the performance of protein disorder prediction programs in detecting changes to disorder caused by amino acid substitutions. We assessed the quality of 29 protein disorder predictors and versions with 101 amino acid substitutions, whose effects have been experimentally validated. Disorder predictors detected the true positives at most with 6% success rate and true negatives with 34% rate for variants. The corresponding rates for the wild type forms are 7 and 90%. The analysis revealed that disorder programs cannot reliably predict the effects of substitutions, consequently the tested methods, and possibly similar programs, cannot be recommended for variant analysis without other information indicating to the relevance of disorder. These results inspired us to develop a new method, PON-Diso (http://structure.bmc.lu.se/PON-Diso), for disorder related amino acid substitutions. With 50% success rate for independent test set and 70.5% rate in cross validation it outperforms the evaluated methods. This article is protected by copyright. All rights reserved.
- TCIRG1 Associated Congenital Neutropenia. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 17.
Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect co-segregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.
- The TP53 Gene Network in a Post-Genomic Era. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 17.
In 2003, Human Mutation published its first special issue on TP53 (Soussi, 2003; http://onlinelibrary.wiley.com/doi/10.1002/humu.v21:3/issuetoc). That issue included the most exhaustive series of reviews devoted to the analysis of TP53 mutations in various types of cancer ever published. Furthermore, thanks to the expertise of the various authors, the quality of the data makes those reviews still highly accurate and up to date.
- Recommendations for Analyzing and Reporting TP53 Gene Variants in the High Throughput Sequencing Era. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 12.
The architecture of TP53, the most frequently mutated gene in human cancer, is more complex than previously thought. Using TP53 variants as clinical biomarkers to predict response to treatment or patient outcome requires an unequivocal and standardized procedure towards a definitive strategy for the clinical evaluation of variants to provide maximum diagnostic sensitivity and specificity. An intronic promoter and two novel exons have been identified resulting in the expression of multiple transcripts and protein isoforms. These regions are additional targets for mutation events impairing the tumor suppressive activity of TP53. Reassessment of variants located in these regions is needed to refine their prognostic value in many malignancies. We recommend using the stable Locus Reference Genomic (LRG) reference sequence for detailed and unequivocal reports and annotations of germ line and somatic alterations on all TP53 transcripts and protein isoforms according the recommendations of the Human Genome Variation Society. This novel and comprehensive description framework will generate standardized data that are easy to understand, analyze and exchange across various cancer variant databases. Based on statistical analysis of more than 45,000 variants in the latest version of the UMD TP53 database, we also provide a classification of their functional effects ("pathogenicity"). This article is protected by copyright. All rights reserved.
- A Dominant Mutation in the Stereocilia-expressing Gene TBC1D24 is a Probable Cause for Non-syndromic Hearing Impairment. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 11.
Mutations in TBC1D24 have been linked to a variety of epileptic syndromes and recently to syndromic hearing impairment DOORS syndrome and non-syndromic hearing impairment DFNB86. All TBC1D24 mutations reported so far were inherited in the recessive mode. In a dominant family segregated with late-onset, progressive, non-syndromic hearing impairment, linkage analysis revealed a 2.07 Mb candidate region on chromosome 16p13.3 that contains TBC1D24. Whole-exome sequencing identified a heterozygous p.Ser178Leu variant of TBC1D24 as the only candidate mutation segregating with the hearing loss within the family. In perinatal mouse cochlea, we detected a restricted expression of Tbc1d24 in the stereocilia of the hair cells as well as in the spiral ganglion neurons. Our study suggested that the p.Ser178Leu mutation of TBC1D24 is a probable cause for dominant, non-syndromic hearing impairment. Identification of TBC1D24 as the stereocilia-expressing gene may shed new light on its specific function in the inner ear. This article is protected by copyright. All rights reserved.
- TBC1D24 Mutation Causes Autosomal Dominant Non-Syndromic Hearing Loss. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 11.
Hereditary hearing loss (HHL) is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal dominant non-syndromic hearing loss (ADNSHL) we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole exome sequencing (WES) to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase-activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL (ARNSHL), syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation and seizures (DOORS syndrome), and a wide range of epileptic disorders. This article is protected by copyright. All rights reserved.
- Germline TP53 Mutations and the Changing Landscape of Li-Fraumeni Syndrome. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 4.
Since its description by Li and Fraumeni over 40 years ago, Li-Fraumeni syndrome (LFS) remains one of the most striking familial cancer predisposition syndromes. Children and adults are affected by a wide array of cancers that occur predominantly at younger ages. This review discusses LFS, describes its association with TP53, and examines the classic and evolving definitions of the syndrome. The potential implications of multi-gene assessments of individuals at increased cancer risk, which have already begun to identify individuals with very little personal or family cancer history carrying germline TP53 mutations, are considered. Newer options in the management of individuals with LFS are also discussed, highlighting the importance of further clinical trials for cancer detection, prevention and management. Finally, we observe how the clinical criteria for TP53 mutation screening appear to be evolving as our understanding of the impact of germline TP53 mutations continues to expand. This article is protected by copyright. All rights reserved.
- Analysis of TP53 Mutation Status in Human Cancer Cell Lines: A Reassessment. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 2.
Tumor-derived cell lines play an important role in the investigation of tumor biology and genetics. Across a wide array of studies, they have been tools of choice for the discovery of important genes involved in cancer and for the analysis of the cellular pathways that are impaired by diverse oncogenic events. They are also invaluable for screening novel anticancer drugs. The TP53 protein is a major component of multiple pathways that regulate cellular response to various types of stress. Therefore, TP53 status effects the phenotype of tumor cell lines profoundly and must be carefully ascertained for any experimental project. In the present review, we use the 2014 release of the UMD TP53 database to show that TP53 status is still controversial for numerous cell lines, including some widely used lines from the NCI-60 panel. Our analysis clearly confirms that, despite numerous warnings, the misidentification of cell lines is still present as a silent and neglected issue, and that extreme care must be taken when determining the status of p53, because errors may lead to disastrous experimental interpretations. A novel compendium gathering the TP53 status of 2,500 cell lines has been made available (http://p53.fr). A stand-alone application can be used to browse the database and extract pertinent information on cell lines and associated TP53 mutations. It will be updated regularly to minimize any scientific issues associated with the use of misidentified cell lines (http://p53.fr). This article is protected by copyright. All rights reserved.
- Cantú Syndrome Resulting from Activating Mutation in the KCNJ8 Gene. [JOURNAL ARTICLE]
- Hum Mutat 2014 Apr 2.
ATP-sensitive potassium (KATP ) channels, composed of inward-rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome, a distinct multi-organ disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation-negative patient who also exhibited clinical hallmarks of Cantú syndrome (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity, whether co-expressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in Cantú syndrome, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from Kir6-independent SUR2 function. This article is protected by copyright. All rights reserved.