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1.
Genes Chromosomes Cancer ; 54(9): 575-82, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26171675

ABSTRACT

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder predisposing to gastrointestinal hamartomatous polyps and cancer with a pathogenic SMAD4 or BMPR1A germline mutation (1st-hit) being identified in about 40-50% of patients. Little is known, however, about the occurrence and nature of somatic alterations (2nd-hit) in SMAD4-/BMPR1A-related juvenile polyps. In this study, we screened 25 polyps from three patients carrying either a pathogenic SMAD4 (c.1244-1247delACAG) or BMPR1A (c.583C>T; p.Gln195*) germline mutation for somatic alterations. The SMAD4-related polyps were also analyzed for SMAD4 protein expression by immunohistochemistry. Despite comprehensive screening for loss of heterozygosity (LOH), mutations in the coding sequence, chromosomal rearrangements, and promoter methylation, no somatic alterations could be identified in 14 SMAD4-related polyps. SMAD4 protein expression, however, was lost in 8 (57%) of 14 juvenile polyps with 6 showing concomitant loss in both, the epithelial and stromal, compartments. In the BMPR1A-related polyps, five out of nine (56%) displayed LOH. Further analysis of selected polyps revealed that LOH was gene copy number neutral and had occurred in the epithelial compartment. The heterogeneity of genetic mutations and protein expression levels indicates that different modes of gene inactivation can be operational in SMAD4- and BMPR1A-related polyp formation. Our observation, that about half of BMPR1A-related polyps displayed LOH, predominantly in the epithelial compartment, is compatible with BMPR1A acting as a tumour suppressor gene. Still, it remains to be determined whether juvenile polyp development generally requires loss of BMPR1A expression or, as observed in some SMAD4-related polyps, can occur despite normal protein expression.


Subject(s)
Bone Morphogenetic Protein Receptors, Type I/genetics , Intestinal Polyposis/congenital , Mutation , Neoplastic Syndromes, Hereditary/genetics , Smad4 Protein/genetics , Adult , Humans , Intestinal Polyposis/genetics , Intestinal Polyposis/metabolism , Loss of Heterozygosity , Neoplastic Syndromes, Hereditary/metabolism , Smad4 Protein/metabolism
2.
PLoS One ; 6(6): e21433, 2011.
Article in English | MEDLINE | ID: mdl-21738662

ABSTRACT

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNA(K542N/K542N) patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS.


Subject(s)
Lamin Type A/genetics , Lamin Type A/metabolism , Progeria/genetics , Progeria/metabolism , Blotting, Western , Cells, Cultured , Child , Fluorescent Antibody Technique , Gene Expression Profiling , Humans , Male , Osteoprotegerin/genetics , Osteoprotegerin/metabolism , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/metabolism , Pyrophosphatases/genetics , Pyrophosphatases/metabolism , Real-Time Polymerase Chain Reaction , Repressor Proteins/genetics , Repressor Proteins/metabolism , Twist-Related Protein 1/genetics , Twist-Related Protein 1/metabolism , Young Adult
3.
Hum Mutat ; 30(3): E500-19, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19105190

ABSTRACT

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.


Subject(s)
Agenesis of Corpus Callosum , Gene Deletion , Mutation , Proteins/genetics , Spastic Paraplegia, Hereditary/genetics , Adolescent , Adult , Algeria , Base Sequence , Brazil , DNA Mutational Analysis , Family Health , Female , Gene Frequency , Genes, Recessive , Genetic Testing , Genotype , Haplotypes , Humans , Male , Middle Aged , Morocco , Pedigree , Portugal , Spastic Paraplegia, Hereditary/diagnosis , Spastic Paraplegia, Hereditary/ethnology , Young Adult
4.
Acta Otolaryngol ; 128(10): 1056-62, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18607988

ABSTRACT

CONCLUSION: Biallelic Cx26 mutations are the most common cause of autosomal recessive nonsyndromic hearing impairment (ARNHI) in Switzerland. Mutations in Cx30 and 31, digenic mutations as well as large deletions/duplications, are unlikely to be a major cause of hearing loss in Swiss patients with ARNHI. Multiplex ligation-dependent probe amplification (MLPA) is a highly accurate screening method for detection of c.del(GJB6-D13S1830). OBJECTIVES: The intent of this study was to investigate the prevalence of the point and digenic mutations including large deletions and duplications in the Cx26, 30, and 31 genes in a Swiss patient cohort with ARNHI and cochlear implant. PATIENTS AND METHODS: The coding regions of Cx26, 30, and 31 were sequenced in 32 patients. Large deletions/duplications were assessed by MLPA. RESULTS: In one patient digenic heterozygous mutations involving Cx26 (c.35delG) and Cx30 (c.del(GJB6-D13S1830)) were identified. Biallelic Cx26 mutations were detected in 31%. One putative mutation (c.94C>T) was found in Cx31. MLPA analysis did not reveal any additional deletion or duplication in all three Cx genes, except for the heterozygous c.del(GJB6-D13S1830) deletion.


Subject(s)
Connexins/genetics , DNA Mutational Analysis , Deafness/genetics , Case-Control Studies , Cochlear Implants , Cohort Studies , Connexin 26 , Deafness/surgery , Gene Deletion , Gene Frequency , Genotype , Humans , Mutation , Polymerase Chain Reaction , Polymorphism, Genetic , Sensitivity and Specificity
5.
Genes Chromosomes Cancer ; 45(12): 1106-10, 2006 Dec.
Article in English | MEDLINE | ID: mdl-16955466

ABSTRACT

Hereditary nonpolyposis colorectal cancer is an autosomal dominant cancer predisposition syndrome caused by inherited germ line mutations in DNA mismatch repair genes, predominantly MSH2 and MLH1. Here we report the first proven de novo germ line mutation in MLH1 (c.666dupA) identified in a 31-year-old colorectal cancer patient with the alteration being present in a heterozygous state in all three germ layers and homozygously in his colon cancer. The mutation was absent in both biological parents and all sibs available. Despite extensive polymorphic marker analysis, the parental origin of c.666dupA could not be conclusively determined, representing either a single mutational event in a parental germ cell or (maternal) gonadal mosaicism. Although rare, consequential application of the Bethesda guidelines for genetic testing should allow the clinician to readily identify colorectal cancer patients below age 50 years who carry de novo mismatch repair gene mutations.


Subject(s)
Adenocarcinoma/genetics , Carrier Proteins/genetics , Colorectal Neoplasms/genetics , Germ-Line Mutation , Nuclear Proteins/genetics , Adaptor Proteins, Signal Transducing , Adult , Family , Female , Humans , Male , Middle Aged , MutL Protein Homolog 1
6.
Laryngoscope ; 116(1): 111-4, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16481821

ABSTRACT

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominantly inherited disorder characterized by dysphagia, ptosis, and proximal limb weakness and is caused by germline mutations (triplet repeat expansions) in the polyadenylate binding protein nuclear 1 (PABPN1) gene. OBJECTIVE: To describe a 70-year-old female patient with OPMD on the clinical and molecular genetic level and to develop a rapid and efficient molecular genetic screening method to study large patient groups. METHODS: Detailed family history and clinical assessment of the OPMD patient were followed by mutation analysis of the PABPN1 gene by direct DNA sequencing and by our newly developed method, fluorescent PABPN1 polymerase chain reaction (PCR) product (flPPP) method. A cohort of 50 healthy Swiss probands was screened using the flPPP to assess the frequency of the (GCG)7 allele in the Swiss population. Cricopharyngeal myotomy was performed as treatment for dysphagia. RESULTS: A heterozygous (GCG)9 triplet repeat expansion in PABPN1 was identified. Since the family history proved to be negative, the mutation is likely to have occurred de novo. The frequency of the (GCG)7 allele among healthy Swiss controls amounted to 1%. The flPPP method showed a sensitivity and specificity of 100%. Two years after cricopharyngeal myotomy, the patient is still relieved of dysphagia. CONCLUSIONS: An otolaryngologist should include OPMD in the differential diagnosis of a patient presenting with dysphagia, as this symptom can be the first sign of the disease and family history can be negative. Molecular genetic testing represents a highly accurate and rapid way to confirm the clinical diagnosis of OPMD. Cricopharyngeal myotomy relieves the patient of dysphagia in the majority of cases.


Subject(s)
Germ-Line Mutation , Muscular Dystrophy, Oculopharyngeal/diagnosis , Muscular Dystrophy, Oculopharyngeal/genetics , Pharyngeal Muscles/surgery , Poly(A)-Binding Protein I/genetics , Aged , DNA Mutational Analysis , Deglutition Disorders/diagnosis , Deglutition Disorders/etiology , Female , Follow-Up Studies , Genetic Predisposition to Disease , Humans , Risk Assessment , Treatment Outcome
7.
Cancer Res ; 66(2): 659-64, 2006 Jan 15.
Article in English | MEDLINE | ID: mdl-16423994

ABSTRACT

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPCC tumorigenesis, commonly referred to as loss of heterozygosity. Here, we applied a recently developed method, multiplex ligation-dependent probe amplification, to study MLH1/MSH2 copy number changes in 16 unrelated Swiss HNPCC patients, whose cancers displayed microsatellite instability and loss of MLH1 or MSH2 expression, but in whom no germ line mutation could be detected by conventional screening. The aims of the study were (a) to determine the proportion of large genomic rearrangements among Swiss MLH1/MSH2 mutation carriers and (b) to investigate the frequency and nature of loss of heterozygosity as a second, somatic event, in tumors from MLH1/MSH2 germ line deletion carriers. Large genomic deletions were found to account for 4.3% and 10.7% of MLH1 and MSH2 mutations, respectively. Multiplex ligation-dependent probe amplification analysis of 18 cancer specimens from two independent sets of Swiss and Finnish MLH1/MSH2 deletion carriers revealed that somatic mutations identical to the ones in the germ line occur frequently in colorectal cancers (6 of 11; 55%) and are also present in extracolonic HNPCC-associated tumors. Chromosome-specific marker analysis implies that loss of the wild-type allele predominantly occurs through locus-restricted recombinational events, i.e., gene conversion, rather than mitotic recombination or deletion of the respective gene locus. (Cancer Res 2006; (66)2: 659-64).


Subject(s)
Carrier Proteins/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Gene Conversion , Loss of Heterozygosity , MutS Homolog 2 Protein/genetics , Nuclear Proteins/genetics , Adaptor Proteins, Signal Transducing , Adult , Aged , Cell Transformation, Neoplastic , DNA Mutational Analysis , Female , Finland , Gene Deletion , Gene Dosage , Gene Expression Profiling , Genetic Predisposition to Disease , Germ-Line Mutation , Humans , Male , Microsatellite Repeats , Middle Aged , MutL Protein Homolog 1 , Switzerland
8.
Hum Genet ; 116(6): 461-5, 2005 May.
Article in English | MEDLINE | ID: mdl-15772852

ABSTRACT

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited, colorectal cancer (CRC) predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 and MSH2. Thus far, only limited data exist on the occurrence of genetic anticipation in HNPCC, i.e. the earlier age at diagnosis of CRC in successive generations. Performing nonparametric distribution-free statistical analyses, we investigated 55 parent-child pairs who had been diagnosed with CRC and who came from 21 Swiss HNPCC families with characterised MMR germline mutation (15 in MLH1 and 6 in MSH2). The overall median age at diagnosis was 43 years, with an interquartile range (IQR) of 14 and incidence ages ranging from 18 to 62 years. Descendants of HNPCC patients (median age at diagnosis 39 years, IQR=12) were found to be diagnosed with CRC significantly earlier than their parents (47 years, IQR=10), with the median of the paired age difference amounting to 8 years (IQR=15; P<0.0001). Birth cohort effects could be excluded, since the same, statistically significant, age difference was also observed in the oldest offspring birth cohort (birth year <1916; P=0.01). Genetic anticipation appeared to be more pronounced when the disease allele was transmitted through the father than through the mother (median age difference 11 vs. 4 years, respectively; both P<0.01). If confirmed in larger, ideally prospective studies, these results may have important implications for genetic counselling and clinical management of HNPCC families.


Subject(s)
Anticipation, Genetic , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Adolescent , Adult , Age of Onset , Fathers , Female , Germ-Line Mutation , Humans , Male , Middle Aged
9.
Recent Results Cancer Res ; 163: 235-47; discussion 264-6, 2003.
Article in English | MEDLINE | ID: mdl-12903858

ABSTRACT

Strategies of cancer prevention are generally developed with the population at large in mind. However, special attention is warranted for those persons with rare genetic traits associated with a greatly elevated risk of developing colorectal cancer (CRC) and some other malignancies: Orphan diseases demand Orphan preventive measures! Recent advances in modern genetics have enhanced our understanding of several genes and the specific germ-line mutations responsible for colorectal carcinogenesis. A number of features provide evidence for a genetic predisposition to CRC. These include typical clinical and histological features of a particular syndrome, a familial aggregation of CRC and associated malignancies, young age at onset of CRC, occurrence of multiple neoplasias and/or unusual localisation of the tumour (e.g., right side of the colon). In hereditary colorectal cancer, genetic testing can easily be demonstrated as cost-effective.


Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , Genetic Predisposition to Disease , Antineoplastic Agents/therapeutic use , Chemoprevention , Genetic Testing , Humans , Mass Screening , Neoplasm Proteins
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