Schizophrenia is a common mental disease characterized by delusions, hallucinations, and formal thought disorder. It has been demonstrated with genetic evidence that the disease is a polygenic disorder. Pharmacological, neurochemical, and clinical studies have suggested a number of schizophrenia susceptibility loci. In order to systematically search for genes with small effect in the development of schizophrenia, a database called VSD was established to provide variation data for publicly available candidate genes. Most of the genes encode neurotransmitter receptors, neurotransmitter transporters, and the enzymes involved in their metabolism. Other candidate genes extracted from published literature are also included. The variation information has been collected from publicly available mutation and polymorphism databases such as dbSNP, HGVbase, and OMIM, with single nucleotide polymorphism (SNP) being the most abundant form of collected variations. Reference sequences from NCBI's RefSeq database are used as references when positioning variation at transcript and protein levels. The nonsynonymous SNPs (nsSNPs) that lead to amino acid changes in the functional sites or domains of proteins are distinguished since they are more likely to affect protein function and would be target SNPs for association studies. In addition to variation data, gene descriptions, enzyme information, and other biological information for each gene locus are also included. The latest version of VSD contains 23,648 variations assigned to a total of 186 genes. Five‐hundred eighty‐eight domains and sites annotated in the SWISS‐PROT and InterPro databases are found to contain nsSNPs. VSD may be accessed via the World Wide Web (www.chgb.org.cn/vsd.htm) and will be developed as an up‐to‐date and comprehensive locus‐specific resource for identifying susceptibility genes for schizophrenia. Hum Mutat 23:1–7, 2004. © 2003 Wiley‐Liss, Inc.

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Allelic genes of blood group antigens: A source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database

Blumenfeld, Olga O.; Patnaik, Santosh K.

2004 Human Mutation

doi: 10.1002/humu.10296pmid: 14695527

In this report, we analyze data assembled in the Blood Group Antigen Gene Mutation Database (www.bioc.aecom.yu.edu/bgmut/index.htm), which describes sequence information on human genes associated with expression of the various serologically‐determined blood group phenotypes. The database documents 38 genetic loci and a total of 624 alleles that together encode a large repertoire of proteins and constitute 27 serologically‐defined blood group systems. Analysis of sequence variation patterns across alleles of a number of genes is focused on their molecular profiles, including mutational sites and recurrence, patterns of gene rearrangements in duplicated gene families, correlation of predicted location of epitopes in extracellular loops with sites of alterations, and effects of mutations on protein expression. That information, and the relative ease of identifying individuals bearing variant alleles, has led to the proposal that genes encoding blood group antigens are an important and unique resource for studies of human DNA variation. Another focus is on mutations in regions that encode the antigenic epitopes and on their occurrence in world populations. These mutations may be viewed as coding single nucleotide polymorphisms (cSNPs). We propose that one group of these cSNPs, which are known to occur with significant frequency in all world populations, could serve as well‐validated genetic markers. In addition, specific mutations in a number of “low incidence” and rare alleles could serve as cSNPs specific for a given population. The allelic frequencies of these mutations and knowledge of their world‐wide occurrence add a valuable dataset to the existing cSNP pools documented in SNP databases. Hum Mutat 23:8–16, 2004. © 2003 Wiley‐Liss, Inc.

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Subtelomeric deletions detected in patients with idiopathic mental retardation using multiplex ligation‐dependent probe amplification (MLPA)

Rooms, Liesbeth; Reyniers, Edwin; Luijk, Rob van; Scheers, Stefaan; Wauters, Jan; Ceulemans, Berten; Van Den Ende, Jenneke; Van Bever, Yolande; Kooy, R. Frank

2004 Human Mutation

doi: 10.1002/humu.10300pmid: 14695528

Subtelomeric rearrangements are responsible for 5% to 10% of cases of unexplained mental retardation. Despite their clinical relevance, methods to screen for these cytogenetically invisible abnormalities on a routine base are scarce. We screened patients with idiopathic mental retardation for subtelomeric aberrations using multiplex ligation‐dependent probe amplification (MLPA). This recently developed technique is based on PCR amplification of ligated probes hybridized to chromosome ends. Currently, 41 telomeres can be screened in just two multiplex reactions. Four subtelomeric rearrangements (5.3%) were detected in a group of 75 patients with mild to severe mental retardation in combination with dysmorphic features and/or a familial history of mental retardation: two terminal 1p deletions, a terminal 1q deletion, and a terminal 3p deletion. Deletions could be verified by FISH and marker analysis. In one case the MLPA indicated a terminal 21q deletion due to a 3‐bp deletion at the site of the probe, giving a false‐positive rate of 1.3%. This study demonstrates that MLPA is a fast and reliable screening method, potentially suitable for use in routine diagnostics. Hum Mutat 23:17–21, 2004. © 2003 Wiley‐Liss, Inc.

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Interaction between trypsinogen isoforms in genetically determined pancreatitis: Mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2)

Teich, Niels; Le Maréchal, Cédric; Kukor, Zoltán; Caca, Karel; Witzigmann, Helmut; Chen, Jian‐Min; Tóth, Miklós; Mössner, Joachim; Keim, Volker; Férec, Claude; Sahin‐Tóth, Miklós

2004 Human Mutation

doi: 10.1002/humu.10285

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Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus‐mediated expression

Pattison, Susan; Pankarican, Michael; Rupar, C. Anthony; Graham, Frank L.; Igdoura, Suleiman A.

2004 Human Mutation

doi: 10.1002/humu.10278pmid: 14695530

Sialidosis is an autosomal recessive disease resulting from a deficiency of lysosomal sialidase. Type II sialidosis is a rare disease characterized clinically by hydrops fetalis, hepatosplenomegaly, and severe psychomotor retardation. Genomic DNA from four unrelated sialidosis patients was screened for mutations within the sialidase gene NEU1. Five novel mutations were identified. Four are missense and one is nonsense: c.674G>C (p.R225P), c.893C>T (p.A298V), c.3G>A (p.M1?), c.941C>G (p.R341G), and c.69G>A (p.W23X). We have used our findings and diagnostic tools to confirm the presence of a homozygous null allele in a neonate sibling. Recombinant adenoviruses expressing the mutant sialidase alleles in primary cell cultures were utilized to assess the impact of each mutation on enzyme activity and intracellular localization. None of the mutant alleles expressed significant enzymatic activity. The p.R341G mutation exerts its pathological effect by perturbing substrate binding, while the p.A298V and p.R225P mutations appear to impair the folding of the sialidase enzyme. Our findings point to mutation‐sensitive amino acids involved in catalytic function or structural stability and indicate the potential utility of these mutations for molecular diagnosis of this rare disease. Hum Mutat 23:32–39, 2004. © 2003 Wiley‐Liss, Inc.

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Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location

Maranchie, Jodi K.; Afonso, Anoushka; Albert, Paul S.; Kalyandrug, Sivaram; Phillips, John L.; Zhou, Shubo; Peterson, James; Ghadimi, Bijan M.; Hurley, Katheen; Riss, Joseph; Vasselli, James R.; Ried, Thomas; Zbar, Berton; Choyke, Peter; Walther, McClellan M.;

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Twenty‐two novel mutations in the lysosomal α‐glucosidase gene (GAA) underscore the genotype–phenotype correlation in glycogen storage disease type II

Hermans, Monique M.P.; Leenen, Dik van; Kroos, Marian A.; Beesley, Clare E.; Van der Ploeg, Ans T.; Sakuraba, Hitoshi; Wevers, Ron; Kleijer, Wim; Michelakakis, Helen; Kirk, Edwin P.; Fletcher, Janice; Bosshard, Nils; Basel‐Vanagaite, Lina; Besley, Guy;

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DGGE‐based whole‐gene mutation scanning of the dystrophin gene in Duchenne and Becker muscular dystrophy patients

Hofstra, Robert M.W.; Mulder, Inge M.; Vossen, Rolf; de Koning‐Gans, Pia A. M.; Kraak, Marian; Ginjaar, Ieke B.; van der Hout, Annemarie H.; Bakker, Egbert; Buys, Charles H.C.M.; van Ommen, Gert‐Jan B.; van Essen, Anthonie J.; den Dunnen, Johan T.

2004 Human Mutation

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Nonclassical splicing mutations in the coding and noncoding regions of the ATM Gene: Maximum entropy estimates of splice junction strengths

Eng, Laura; Coutinho, Gabriela; Nahas, Shareef; Yeo, Gene; Tanouye, Robert; Babaei, Mahnoush; Dörk, Thilo; Burge, Christopher; Gatti, Richard A.

2004 Human Mutation

doi: 10.1002/humu.10295pmid: 14695534

Ataxia‐telangiectasia (A‐T) is an autosomal recessive neurological disorder caused by mutations in the ATM gene. Classical splicing mutations (type I) delete entire exons during pre‐mRNA splicing. In this report, we describe nine examples of nonclassical splicing mutations in 12 A‐T patients and compare cDNA changes to estimates of splice junction strengths based on maximum entropy modeling. These mutations fall into three categories: pseudoexon insertions (type II), single nucleotide changes within the exon (type III), and intronic changes that disrupt the conserved 3′ splice sequence and lead to partial exon deletion (type IV). Four patients with a previously reported type II (pseudoexon) mutation all shared a common founder haplotype. Three patients with apparent missense or silent mutations actually had type III aberrant splicing and partial deletion of an exon. Five patients had type IV mutations that could have been misinterpreted as classical splicing mutations. Instead, their mutations disrupt a splice site and use another AG splice site located nearby within the exon; they lead to partial deletions at the beginning of exons. These nonclassical splicing mutations create frameshifts that result in premature termination codons. Without screening cDNA or using accurate models of splice site strength, the consequences of these genomic mutations cannot be reliably predicted. This may lead to further misinterpretation of genotype–phenotype correlations and may subsequently impact upon gene‐based therapeutic approaches. Hum Mutat 23:67–76, 2004. © 2003 Wiley‐Liss, Inc.

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Knobloch syndrome: Novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin

Menzel, Olivier; Bekkeheien, Reidunn C.J.; Reymond, Alexandre; Fukai, Naomi; Boye, Eileen; Kosztolanyi, Gyorgy; Aftimos, Salim; Deutsch, Samuel; Scott, Hamish S.; Olsen, Bjorn R.; Antonarakis, Stylianos E.; Guipponi, Michel

2004 Human Mutation

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Nature Genetics Nucleic Acids Research Genetics Annual Review of Genetics Genomics Mammalian Genome Chromosome Research Journal of Genetics Russian Journal of Genetics

pmid:

14695529

The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen. To date, 19 genetic variants have been identified in the cationic trypsinogen gene (PRSS1) of patients with hereditary, familial, or sporadic chronic pancreatitis. A common feature of cationic trypsinogen mutants studied so far is an increased propensity for autocatalytic activation (autoactivation). This is thought to lead to premature intrapancreatic digestive protease activation. In contrast, no pancreatitis‐associated mutations have been found in the anionic trypsinogen gene (PRSS2), suggesting that this isoform might play a relatively unimportant role in pancreatitis. To challenge this notion, here we describe the unique properties of the E79K cationic trypsinogen mutation (c.235G>A), which was identified in three European families affected by sporadic or familial pancreatitis cases. In vitro analysis of recombinant wild‐type and mutant enzymes revealed that catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor was unaffected. Although the E79K mutation introduces a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K‐trypsin was also unchanged. Furthermore, in contrast to previously characterized disease‐causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen two‐fold better than wild‐type cationic trypsin did, while the common pancreatitis‐associated mutants R122H or N29I had no such effect. The observations not only suggest a novel mechanism of action for pancreatitis‐associated trypsinogen mutations, but also highlight the importance of interactions between the two major trypsinogen isoforms in the development of genetically determined chronic pancreatitis. Hum Mutat 23:22–31, 2004. © 2003 Wiley‐Liss, Inc.

Klausner, Richard D.;

Linehan, W. Marston

2004 Human Mutation

doi: 10.1002/humu.10302pmid: 14695531

von Hippel Lindau disease (VHL) is an autosomal dominant familial cancer syndrome linked to alteration of the VHL tumor suppressor gene. Affected patients are predisposed to develop pheochromocytomas and cystic and solid tumors of the kidney, CNS, pancreas, retina, and epididymis. However, organ involvement varies considerably among families and has been shown to correlate with the underlying germline alteration. Clinically, we observed a paradoxically lower prevalence of renal cell carcinoma (RCC) in patients with complete germline deletion of VHL. To determine if a relationship existed between the type of VHL deletion and disease, we retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions, by history and radiographic imaging. Each individual and family was scored for cystic or solid involvement of CNS, pancreas, and kidney, and for pheochromocytoma. Germline deletions were mapped using a combination of fluorescent in situ hybridization (FISH) and quantitative Southern and Southern blot analysis. An age‐adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9 vs. 22.6%, p=0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p=0.22), pancreas (p=0.72), or pheochromocytoma (p=0.34). Deletion mapping revealed that development of RCC had an even greater correlation with retention of HSPC300 (C3orf10), located within the 30‐kb region of chromosome 3p, immediately telomeric to VHL (52.3 vs. 18.9%, p <0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC. Careful correlation of genotypic data with objective phenotypic measures will provide further insight into the mechanisms of tumor formation. Hum Mutat 23:40–46, 2004. © 2003 Wiley‐Liss, Inc.

Reuser, Arnold J.J.

2004 Human Mutation

doi: 10.1002/humu.10286pmid: 14695532

Patients with glycogen storage disease type II (GSDII, Pompe disease) suffer from progressive muscle weakness due to acid α‐glucosidase deficiency. The disease is inherited as an autosomal recessive trait with a spectrum of clinical phenotypes. We have investigated 29 cases of GSDII and thereby identified 55 pathogenic mutations of the acid α‐glucosidase gene (GAA) encoding acid maltase. There were 34 different mutations identified, 22 of which were novel. All of the missense mutations and two other mutations with an unpredictable effect on acid α‐glucosidase synthesis and function were transiently expressed in COS cells. The effect of a novel splice‐site mutation was investigated by real‐time PCR analysis. The outcome of our analysis underscores the notion that the clinical phenotype of GSDII is largely dictated by the nature of the mutations in the GAA alleles. This genotype–phenotype correlation makes DNA analysis a valuable tool to help predict the clinical course of the disease. Hum Mutat 23:47–56, 2004. © 2003 Wiley‐Liss, Inc.

doi: 10.1002/humu.10283pmid: 14695533

Duchenne and Becker muscular dystrophy (DMD and BMD) are caused by mutations in the dystrophin gene. Large rearrangements in the gene are found in about two‐thirds of DMD patients, with ∼60% carrying deletions and 5–10% carrying duplications. Most of the remaining 30–35% of patients are expected to have small nucleotide substitutions, insertions, or deletions. To detect these subtle changes within the coding and splice site determining sequences of the dystrophin gene, we established a semiautomated denaturing gradient gel electrophoresis (DGGE) mutation scanning system. The DGGE scan covers the dystrophin gene with 95 amplicons, PCRed either individually or in a multiplex setup. PCR and pooling were performed semiautomatically, using a pipetting robot and 384‐well plates, enabling concurrent amplification of DNA of four patients in one run. Amplification of individual fragments was performed using one PCR program. The products were pooled just before gel loading; DGGE requires only a single gel condition. Validation was performed using DNA samples harboring 39 known DMD variants, all of which could be readily detected. DGGE mutation scanning was applied to analyze 135 DMD/BMD patients and potential DMD carriers without large deletions or duplications. In DNA from 25 out of 44 DMD patients (57%) and from 5 out of 39 BMD patients (13%), we identified clear pathogenic changes. All mutations were different, with the exception of one DMD mutation, which occurred twice. In DNA from 10 out of 44 potential DMD carriers, including four obligate carriers, we detected causative changes, including one pathogenic change in every obligate carrier. In addition to these pathogenic changes, we detected 15 unique unclassified variants, i.e., changes for which a pathogenic nature is uncertain. Hum Mutat 23:57–66, 2004. © 2003 Wiley‐Liss, Inc.

doi:

10.1002/humu.10284

pmid:

14695535

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by high myopia, vitreoretinal degeneration with retinal detachment, and congenital encephalocele. Pathogenic mutations in the COL18A1 gene on 21q22.3 were recently identified in KNO families. Analysis of two unrelated KNO families from Hungary and New Zealand allowed us to confirm the involvement of COL18A1 in the pathogenesis of KNO and to demonstrate the existence of genetic heterogeneity. Two COL18A1 mutations were identified in the Hungarian family: a 1‐bp insertion causing a frameshift and a premature in‐frame stop codon and an amino acid substitution. This missense variant is located in a conserved amino acid of endostatin, a cleavage product of the carboxy‐terminal domain of collagen alpha 1 XVIII. D1437N (D104N in endostatin) likely represents a pathogenic mutation, as we show that the endostatin N104 mutant is impaired in its affinity towards laminin. Linkage to the COL18A1 locus was excluded in the New Zealand family, providing evidence for the existence of a second KNO locus. We named the second unmapped locus for Knobloch syndrome KNO2. Mutation analysis excluded COL15A1, a member of the multiplexin collagen subfamily similar to COL18A1, as being responsible for KNO2. Hum Mutat 23:77–84, 2004. © 2003 Wiley‐Liss, Inc.