Limb-girdle muscular dystrophy 1F is caused by a microdeletion in the transportin 3 gene

In 2001, we reported linkage of an autosomal dominant form of limb-girdle muscular dystrophy, limb-girdle muscular dystrophy 1F, to chromosome 7q32.1-32.2, but the identity of the mutant gene was elusive. Here, using a whole genome sequencing strategy, we identified the causative mutation of limb-girdle muscular dystrophy 1F, a heterozygous single nucleotide deletion (c.2771del) in the termination codon of transportin 3 (TNPO3). This gene is situated within the chromosomal region linked to the disease and encodes a nuclear membrane protein belonging to the importin beta family. TNPO3 transports serine/arginine-rich proteins into the nucleus, and has been identified as a key factor in the HIV-import process into the nucleus. The mutation is predicted to generate a 15-amino acid extension of the C-terminus of the protein, segregates with the clinical phenotype, and is absent in genomic sequence databases and a set of >200 control alleles. In skeletal muscle of affected individuals, expression of the mutant messenger RNA and histological abnormalities of nuclei and TNPO3 indicate altered TNPO3 function. Our results demonstrate that the TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expand our knowledge of the molecular basis of muscular dystrophies and bolster the importance of defects of nuclear envelope proteins as causes of inherited myopathies

New genes emerging for colorectal cancer predisposition.

Colorectal cancer (CRC) is one of the most frequent neoplasms and an important cause of mortality in the developed world. This cancer is caused by both genetic and environmental factors although 35% of the variation in CRC susceptibility involves inherited genetic differences. Mendelian syndromes account for about 5% of the total burden of CRC, with Lynch syndrome and familial adenomatous polyposis the most common forms. Excluding hereditary forms, there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause. CRC can be also considered as a complex disease taking into account the common disease-commom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect. So far, 30 common, low-penetrance susceptibility variants have been identified for CRC. Recently, new sequencing technologies including exome- and whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition. By using whole-genome sequencing, germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis

TOPIC HIGHLIGHT New genes emerging for colorectal cancer predisposition

Abstract Colorectal cancer (CRC) is one of the most frequent neoplasms and an important cause of mortality in the developed world. This cancer is caused by both genetic and environmental factors although 35% of the variation in CRC susceptibility involves inherited genetic differences. Mendelian syndromes account for about 5% of the total burden of CRC, with Lynch syndrome and familial adenomatous polyposis the most common forms. Excluding hereditary forms, there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause. CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/ moderate effect. So far, 30 common, low-penetrance susceptibility variants have been identified for CRC. Recently, new sequencing technologies including exomeand whole-genome sequencing have permitted to add New genes emerging for colorectal cancer predisposition World J Gastroenterol 2014 February 28; 20(8): 1961-1971 ISSN 1007-9327 (print) ISSN 2219-2840 © 2014 Baishideng Publishing Group Co., Limited. All rights reserved. Esteban-Jurado C et al . New genes for colorectal cancer predisposition a new approach to facilitate the identification of new genes responsible for human disease predisposition. By using whole-genome sequencing, germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis

Teenage-onset progressive myoclonic epilepsy due to a familial C9orf72 repeat expansion.

BACKGROUND: The progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously. OBJECTIVE: To identify the causative mutation in a Belgian family where the proband had genetically unexplained PME. RESULTS: We report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions. CONCLUSION: C9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence

New genes emerging for colorectal cancer predisposition

Colorectal cancer (CRC) is one of the most frequent neoplasms and an important cause of mortality in the developed world. This cancer is caused by both genetic and environmental factors although 35% of the variation in CRC susceptibility involves inherited genetic differences. Mendelian syndromes account for about 5% of the total burden of CRC, with Lynch syndrome and familial adenomatous polyposis the most common forms. Excluding hereditary forms, there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause. CRC can be also considered as a complex disease taking into account the common disease-commom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect. So far, 30 common, low-penetrance susceptibility variants have been identified for CRC. Recently, new sequencing technologies including exome- and whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition. By using whole-genome sequencing, germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.Supported by SCB is supported by a contract from the Fondo de Investigación Sanitaria, No. CP 03-0070; CEJ and JM are supported by a contract from CIBERehd; CIBERehd and CIBERER are funded by the Instituto de Salud Carlos III; Fondo de Investigación Sanitaria/FEDER, No.11/00219 and No. 11/00681, Instituto de Salud Carlos III (Acción Transversal de Cáncer), Xunta de Galicia, No. 07PXIB9101209PR, Ministerio de Ciencia e Innovación, No. SAF2010-19273, Asociación Española contra el Cáncer (Fundación Científica GCB13131592CAST y Junta de Barcelona), Fundació Olga Torres (SCB and CRP), FP7 CHIBCHA Consortium (SCB and ACar), and COST Action BM1206 (SCB and CRP)

New genes emerging for colorectal cancer predisposition.

Colorectal cancer (CRC) is one of the most frequent neoplasms and an important cause of mortality in the developed world. This cancer is caused by both genetic and environmental factors although 35% of the variation in CRC susceptibility involves inherited genetic differences. Mendelian syndromes account for about 5% of the total burden of CRC, with Lynch syndrome and familial adenomatous polyposis the most common forms. Excluding hereditary forms, there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause. CRC can be also considered as a complex disease taking into account the common disease-commom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect. So far, 30 common, low-penetrance susceptibility variants have been identified for CRC. Recently, new sequencing technologies including exome- and whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition. By using whole-genome sequencing, germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis

Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease

Background Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein. Methods We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations. Results After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein. Conclusions We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1