New PRSS1 and common CFTR mutations in a child with acute recurrent pancreatitis, could be considered an "Hereditary" form of pancreatitis ?

<p>Abstract</p> <p>Background</p> <p>acute recurrent pancreatitis is a complex multigenic disease, the diagnosis is even more difficult when this disease develops in a child.</p> <p>Case Presentation</p> <p>a 6-years old boy, hospitalized with epigastric pain radiating to the back showed high serum levels of serum amylase, lipase, CRP and erythrosedimentation rate. Several similar milder episodes of pain, followed by quick recovery and complete disappearance of symptoms were reported during the previous 13 months. The child was medically treated and after 7 days with normal clinic and laboratory tests was discharged with a hypolipidic diet. All the known aetiologic hypotheses were excluded by anamnestic investigation, clinical observation and biochemical evaluation, whereas, anatomic abnormality were excluded by a secretin stimulated magnetic resonance (MRI). At the last follow-up visit, (11 months later), the child showed a normal body weight and anthropometric profile, without further abdominal pain. Mutation screening for coding regions of <it>PRSS1, SPINK1, CFTR </it>and the new hereditary pancreatitis-associated chymotrypsin C (<it>CTRC</it>) genes showed a novel variation, c.541A > G (p.S181G), in the exon 4 of PRSS1 gene and the classical CF p.F508del mutation in the <it>CFTR. </it>Both mutations were present in his clinically normal mother and absent in the patient's father.</p> <p>Conclusions</p> <p>this report extend the spectrum of PRSS1 mutations, however, the absence of family history of pancreatitis leaves the present case without the hallmark of the hereditary origin of pancreatitis. At the present knowledge it can be only stated that the combined genotype CFTR (F508del)/PRSS1 (S181G) is associated to a mild phenotype of acute recurrent pancreatitis in this child without any further conclusion on its pathogenetic role or prediction on the course of the disease.</p

Implications of Advancing Paternal Age: Does It Affect Offspring School Performance?

Average paternal age is increasing in many high income countries, but the implications of this demographic shift for child health and welfare are poorly understood. There is equivocal evidence that children of older fathers are at increased risk of neurodevelopmental disorders and reduced IQ. We therefore report here on the relationship between paternal age and a composite indicator of scholastic achievement during adolescence, i.e. compulsory school leaving grades, among recent birth cohorts in Stockholm County where delayed paternity is notably common. We performed a record-linkage study comprising all individuals in Stockholm County who finished 9 years of compulsory school from 2000 through 2007 (n = 155,875). Data on school leaving grades and parental characteristics were retrieved from administrative and health service registers and analyzed using multiple linear regression. Advancing paternal age at birth was not associated with a decrease in school leaving grades in adolescent offspring. After adjustment for year of graduation, maternal age and parental education, country of birth and parental mental health service use, offspring of fathers aged 50 years or older had on average 0.3 (95% CI −3.8, 4.4) points higher grades than those of fathers aged 30–34 years. In conclusion, advancing paternal age is not associated with poorer school performance in adolescence. Adverse effects of delayed paternity on offspring cognitive function, if any, may be counterbalanced by other potential advantages for children born to older fathers

Protein farnesylation and disease

Prenylation consists of the addition of an isoprenoid group to a cysteine residue located near the carboxyl terminal of a protein. This enzymatic posttranslational modification is important for the maturation and processing of proteins. Both processes are necessary to mediate protein-protein and membrane-protein associations, in addition to regulating the localisation and function of proteins. The severe phenotype of animals deficient in enzymes involved in both prenylation and maturation highlights the significance of these processes. Moreover, alterations in the genes coding for isoprenylated proteins or enzymes that are involved in both prenylation and maturation processes have been found to be the basis of severe human diseases, such as cancer, neurodegenerative disorders, retinitis pigmentosa, and premature ageing syndromes. Recent studies on isoprenylation and postprenylation processing in pathological conditions have unveiled surprising aspects of these modifications and their roles in different cellular pathways. The identification of these enzymes as therapeutic targets has led researchers to validate their effects in vitro and in vivo as antitumour or antiageing agents. This review attempts to summarise the basic aspects of protein isoprenylation and postprenylation, integrating our data with that observed in other studies to provide a comprehensive scenario of progeroid syndromes and the therapeutic avenues

Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24

Mandibuloacral dysplasia (MAD) is a rare recessively inherited premature aging disease characterized by skeletal and metabolic anomalies. It is part of the spectrum of diseases called laminopathies and results from mutations in genes regulating the synthesis of the nuclear laminar protein, lamin A. Homozygous or compound heterozygous mutations in the LMNA gene, which encodes both the precursor protein prelamin A and lamin C, are the commonest cause of MAD type A. In a few cases of MAD type B, mutations have been identified in the ZMPSTE24 gene encoding a zinc metalloproteinase important in the post-translational modification of lamin A. Here we describe a new case of MAD resulting from compound heterozygote mutations in ZMPSTE24 (p.N256S/p.Y70fs). The patient had typical skeletal changes of MAD, but in addition a number of unusual skeletal features including neonatal tooth eruption, amorphous calcific deposits, submetaphyseal erosions, vertebral beaking, severe cortical osteoporosis and delayed fracture healing. Treatment with conventional doses of pamidronate improved estimated volumetric bone density in the spine but did not arrest cortical bone loss. We reviewed the literature on cases of MAD associated with proven LMNA and ZMPSTE24 mutations and found that the unusual features described above were all substantially more prevalent in patients with mutations in ZMPSTE24 than in those with LMNA mutations. We conclude that MAD associated with ZMPSTE24 mutations has a more severe phenotype than that associated with LMNA mutations--probably reflecting the greater retention of unprocessed farnesylated prelamin A in the nucleus, which is toxic to cells

Prenatal diagnosis of Cockayne syndrome type A based on the identification of two novel mutations in the ERCC8 gene

Back Cockayne syndrome (CS; MIM 133540-216400) is a rare autosomal recessive neurodegenerative disorder characterized by progressive growth failure, microcephaly, mental retardation, retinal pigmentary degeneration, deafness, photosensitivity, accelerated systemic degeneration of somatic tissue, and premature death. Complementation assays have defined Cockayne syndrome group A (CSA) and Cockayne syndrome group B (CSB), caused by mutations in ERCC8 and ERCC6. The aim of this work was to perform a molecular analysis in a family with an affected son, who died at the age of 12, presenting clinical features typical of CSA. Molecular analysis of ERCC8 allowed us to characterize two novel mutations: a maternally inherited deletion encompassing exons 5 and 6, and a nonsense mutation located in exon 4, segregating from the father. Based on this molecular characterization, we successively performed a prenatal diagnosis on chorionic villus sampling, at 11th week of pregnancy. Molecular prenatal analysis of the ERCC8 was done by analyzing fetal DNA and RNA, looking for both mutations identified in the proband. A linkage analysis was performed using microsatellite markers located on chromosome 5q11 with the purpose to follow the segregation of the mutated alleles within the family. The fetal genotype at CSA locus resulted wild type and was confirmed at birth on biological material isolated from placenta. This study documents for the first time a molecular prenatal diagnosis of CSA, which results in the preferred approach if the mutation within the family is identified in a timely manner

Carrier frequency of CFTR variants in the non-Caucasian populations by genome aggregation database (gnomAD)-based analysis

The complexity in the molecular diagnosis of Cystic Fibrosis (CF) also depends on the variable prevalence/incidence of the disease associated with the wide CFTR allelic heterogeneity among different populations. In fact, CF incidence in Asian and African countries is underestimated and the few patients reported so far have rare or unique CFTR pathogenic variants. To obtain insights into CF variants profile and frequency, we used the large population sequencing data in the Genome Aggregation Database (gnomAD). We selected 207 CF-causing/varying clinical consequence variants from CFTR2 database and additional 15 variants submitted to the ClinVar database. Only 14 of these variants were found in the East-Asian population, while for South-Asian and African populations we identified 43 and 52 variants, respectively, confirming the peculiarity of the CFTR allelic spectrum with only few population-specific variants. These data could be used to optimize CFTR carrier screening in non-Caucasian subjects, choosing between the full gene sequencing and cost and time-effective targeted panels

Somatic and gonadal mosaicism in Hutchinson-Gilford progeria

We have studied a patient with Hutchinson-Gilford progeria (HGP). Sequence analysis of the LMNA gene demonstrated the presence of a c.1824 C > T (p.G608G) mutation, activating a cryptic splice donor site and leading to the formation of a truncated Lamin A protein. All molecularly characterized autosomal dominant HGP cases described so far result from de novo LMNA mutations, mostly originating on the paternal allele and are often linked with advanced paternal age. However, in our patient, the mutation was transmitted by the mother who showed somatic and germline mosaicism without HGP manifestations. (c) 2005 Wiley-Liss, Inc

Analysis of TNF-alpha promoter polymorphisms in the susceptibility to beryllium hypersensitivity

Background and aim of the work: In susceptible individuals beryllium (Be)-exposure may cause Be-hypersensitivity (BH), leading to a spectrum of immune abnormalities ranging from the systemic responsiveness to Be to the CD4+ T-cell dominated chronic granulomatous pneumonitis known as berylliosis. Two gene markers have been previously associated with berylliosis: HLA-DP allelic variants carrying glutamate in position 69 of the B-chain and the high TNF-alpha production-associated TNF-alpha promoter allele TNFA2. Since a number of TNF-alpha promoter sequence variants have been associated with higher or lower gene-expression, the entire TNF-alpha promoter region was screened for BH-associated variants. Methods: Denaturating High Performance Liquid Chromatography (DHPLC) analysis followed by DNA sequence analysis of the heteroduplex observed was performed on a DNA bank obtained from a Be-exposed population composed of 73 subjects with BH and 43 Be-exposed controls. Results: The data show that the TNF-alpha TNFA2 variant (genotypic frequency: BH 26.7%, Be-exposed controls 5.8%; p < 0.0001), the -857T variant (BH 19.7%, Be-exposed controls 10.5%; p = 0.045) are significantly associated with BH and there is no linkage disequilibrium between them. Further, 64.4% of BH subjects carried at least one of higher TNF-alpha production-associated polymorphisms (Be-exposed controls 34.8%; p = 0.0036). Conclusions: The finding that TNF-alpha production-associated polymorphisms are carried at higher frequency by BH-affected compared to Be-exposed controls suggests that the TNF-alpha may play a central role in the determination of susceptibility to BH

Segregation analysis in cystic fibrosis at-risk family demonstrates that the M348K CFTR mutation is a rare innocuous polymorphism

Objective Cystic fibrosis (CF; OMIM# 219700) is caused by mutation in the CF transmembrane regulator (CFTR) gene. We investigate whether the (paternal) M348K mutation is a benign polymorphism or a disease-causing mutation in a patient clinically affected with CF, with the second (maternal) CFTR allele identified as N1303K. Methods The patient and his father were studied for the presence of mutations in the CFTR gene using the DHPLC system to analyze all CFTR exons. Amplicons showing an abnormal elation profile were sequenced. Results The CFTR gene from the healthy father has two mutations, M348K and G1244E. The affected son inherited only the G1244E paternal mutation from his father, and hence the two paternal mutations are trans and do not occur in the same CFTR gene. The patient's genotype is G1244E(paternal)/Nl3O3K(maternal). This information was used to study an ongoing pregnancy of the couple, where the fetus inherited the same genotype as the affected proband and therefore is affected. Conclusion M348K in the CFTR gene is not a mutation causing CF, but a rare polymorphism. These data are important for genetic counseling and prenatal diagnosis and illustrate the importance of full sequence data when studying rare mutations. Copyright (C) 2004 John Wiley Sons, Ltd