Human Mutation

doi: 10.1002/humu.1380050401pmid: N/A

Smooker, Peter M.; Cotton, Richard G. H.

doi: 10.1002/humu.1380050402pmid: 7627180

The spectrum of mutations causing dihydropteridine reductase is reviewed. A total of 12 point mutations have been described that map in the DHPR cDNA, resulting in amino acid substitutions, insertions and premature terminations. A further two mutations are described which result in aberrant splicing of DHPR transcripts. The application of the mutation identification to diagnostics and clinical treatment is discussed. © 1995 Wiley‐Liss, Inc.

Schuback, Deborah E.; Chen, Zheng Yi; Craig, Ian W.; Breakefield, Xandra O.; Sims, Katherine B.

doi: 10.1002/humu.1380050403pmid: 7627181

We report our experience to date in mutation identification in the Norrie disease (ND) gene. We carried out mutational analysis in 26 kindreds in an attempt to identify regions presumed critical to protein function and potentially correlated with generation of the disease phenotype. All coding exons, as well as noncoding regions of exons 1 and 2, 636 nucleotides in the noncoding region of exon 3, and 197 nucleotides of 5′ flanking sequence, were analyzed for single‐strand conformation polymorphisms (SSCP) by polymerase chain reaction (PCR) amplification of genomic DNA. DNA fragments that showed altered SSCP band mobilities were sequenced to locate the specific mutations. In addition to three previously described submicroscopic deletions encompassing the entire ND gene, we have now identified 6 intragenic deletions, 8 missense (seven point mutations, one 9‐bp deletion), 6 nonsense (three point mutations, three single bp deletions/frameshift) and one 10‐bp insertion, creating an expanded repeat in the 5′ noncoding region of exon 1. Thus, mutations have been identified in a total of 24 of 26 (92%) of the kindreds we have studied to date. With the exception of two different mutations, each found in two apparently unrelated kindreds, these mutations are unique and expand the genotype database. Localization of the majority of point mutations at or near cysteine residues, potentially critical in protein tertiary structure, supports a previous protein model for norrin as member of a cysline knot growth factor family (Meitinger et al., 1993). Genotype‐phenotype correlations were not evident with the limited clinical data available, except in the cases of larger submicroscopic deletions associated with a more severe neurologic syndrome. This lack of correlation suggests that complex epigenetic factors may play a significant role in the physiological and neurodevelopmental expression of the disease phenotype. Given the remarkable intra‐ and interfamilial variability in hearing and brain dysfunction in this disease, it may be expected that other phenotypic expressions of the disease gene, which do not match the “classical” Norrie phenotype, may be identified in the future. © 1995 Wiley‐Liss, Inc.

Tuchman, Mendel; Plante, Robert J.

doi: 10.1002/humu.1380050404pmid: 7627182

This mutation update addendum summarizes 30 new mutations and polymorphisms found in the ornithine transcarbamylase (OTC) gene since the publication in this journal of the first mutation update. Thus, more than 60 mutations and polymorphisms in the OTC gene are currently known. Most of the mutations have been seen in a single family and the few recurrent mutations occurred in CpG dinucleotides. The presumed deleterious effects of most mutations await confirmation by appropriate expression studies. Once the tertiary structure of the enzyme is fully known, and the functional domains established, the effects of mutations, or lack thereof, could be better predicted.© 1995 wiley‐Liss, Inc.

Hagemann, Tracy L.; Rosen, Fred S.; Kwan, Sau‐Ping

doi: 10.1002/humu.1380050405pmid: 7627183

Bruton's tyrosine kinase (Btk) has been identified as the protein responsible for the primary immunodeficiency X‐linked agammaglobulinemia (XLA) and has been described as a new member of Srcrelated cytoplasmic protein tyrosine kinases. We have recently characterized the structure of the entire gene encoding Btk and developed a polymerase chain reaction (PCR)‐based assay to detect germline mutations within it. In this report we describe six mutations, five of which are novel, of the Btk gene in patients with XLA and demonstrate the inheritance pattern of the defect within the families of the affected individuals. The mutations found include two nonsense and two missense mutations, a single base deletion at an intron acceptor splice site, and a 16‐bp insertion. A single Strand conformation polymorphism was also found in the 5′ end of intron 8 with the same assay. This technique has provided a powerful tool for direct analysis of the Btk gene for the diagnosis of XLA and carrier detection. The identification of new mutations may eventually reveal the role of Btk in the signaling pathways involved in B‐cell development. © 1995 Wiley‐Liss, Inc.

Cormand, Bru; Vilageliu, Lluïsa; Burguera, José M.; Balcells, Susana; Gonzàlez‐Duarte, Roser; Grinberg, Daniel; Chabás, Amparo

doi: 10.1002/humu.1380050406pmid: 7627184

Gaucher disease is particularly prevalent among Ashkenazi Jews; thus most studies have been reported on this ethnic group. We present the first data on Spanish patients with Gaucher disease and provide one of the first reports on a fairly well defined, large, non‐Jewish population. Eight mutations were analyzed in 35 patients, with different clinical subtypes, by restriction enzyme digestion or allelespecific oligonucleotide (ASO) hybridization, after PCR amplification of genomic DNA. Analysis of the eight mutations allowed identification of 77.2% of the disease alleles, N370S and L444P alone accounting for 70%. Mutation N370S, carried by 31 alleles (44.3%), appeared to be the most prevalent in the Spanish population. The frequency of this mutation and of the N370S/N370S genotype is closer to those described for Ashkenazi Jews than to the frequencies found in other non‐Jewish populations. Mutation L444P, the second most abundant mutation, occurred in 25.7% of the disease alleles. Four alleles carrying mutation D409H (5.7%) were detected in patients of different clinical expression and one RecNciI allele in a type I patient. Mutations 84GG, IVS2 + l, R463C, and RecTL were also screened but were not found in any of our patients. © 1995 Wiley‐Liss, Inc.

Torroni, Antonio; Brown, Michael D.; Lott, Marie T.; Newman, Nancy J.; Wallace, Douglas C.; ,

doi: 10.1002/humu.1380050407pmid: 7627185

Genetic predisposition, particularly specific mitochondrial DNA (mtDNA) backgrounds, has been proposed as a contributing factor in the expression of an epidemic of bilateral optic neuropathy that has affected residents of Cuba since 1991. To substantiate or refute the possibility that specific subsets of mtDNAs could participate in disease expression, we took advantage of the heterogeneous ethnic origin of the Cuban population and the recent identification of a number of mtDNA polymorphisms that appear to be specific for Africans, Native Americans, and Europeans. The screening of both carefully selected people with epidemic neuropathy and control subjects from the Pinar del Rio Province for these polymorphisms revealed that African, Native American, and European mtDNA haplotypes were equally represented among case and control subjects, and suggested that ∼ 50% of Cuban mtDNAs originated from Europeans, 46% from Africans, and 4% from Native Americans. These findings demonstrate that mutations arising in spic mtDNAs are unlikely to play a role in the epidemic neuropathy and indicate that analysis of mtDNA haplotypes can be a valuable tool for assessing the relative maternal contribution of Africans, Native Americans, and Europeans in a mixed population. © 1995 Wiley‐Liss, Inc.

Isoniemi, Annukka; Hietala, Marja; Aula, Pertti; Jalanko, Anu; Peltonen, Leena

doi: 10.1002/humu.1380050408pmid: 7627186

Aspartylglucosaminuria (AGU) is a recessively inherited metabolic disorder caused by the deficiency of a lysosomal enzyme, aspartylglucosaminidase. The worldwide most common mutation causing the disease is the AGUFin, enriched in Finland; all the other known AGU mutations are family‐specific. We developed exon‐specific primers to facilitate mutation search directly from the genomic DNA and identified a novel mutation, designated AGUFin minor, in seven Finnish AGUFincompound heterozygote patients. This deletion/frameshift mutation creates a premature translational termination codon and was shown to result in severely reduced transcript levels as quantified by the solid‐phase minisequencing method. Genealogical data on this novel mutation suggest its relatively recent introduction into the population. The AGU mutations identified so far have been reported to be evenly distributed throughout the 1 kb coding region of the AGA cDNA. We identified a mutation hotspot region of 40 bp within the 12.5 kb AGA gene containing two previously identified mutations and the novel AGUFin minor mutation characterized in this study. © 1995 Wiley‐Liss, Inc.

De Leo, R.; Deidda, G.; Novelletto, A.; El‐Kalla, S.; Mathews, A. R.; Felicetti, L.

doi: 10.1002/humu.1380050409pmid: 7627187

β‐thalassemia mutations were characterized in a sample of 70 patients from United Arab Emirates (U.A.E.), resulting in an enlargement of the spectrum of types found in the country. The complete association between the most common IVS I nt 5 (G‐C) mutation and a specific haplotype reveals an independent origin of this mutation in U.A.E. © 1995 Wiley‐Liss, Inc.

Hoff‐Olsen, Per; Meling, Gunn Iren; Olaisen, Bjørnar

doi: 10.1002/humu.1380050410pmid: 7627188

To elucidate mutation mechanisms in hypervariable VNTR loci, we have studied somatic mutation events with the minisatellite probe MSI (VNTR locus D1S7) in 224 colorectal carcinomas (CRC). The D1 S7 locus consists of a 9‐basepair (bp) repeat unit. The copy number varies from about 100 to 2000, and the germline mutation rate is high. Here we demonstrate a high D1S7 somatic mutation rate in CRC (37/224), higher than indicated earlier by others. We atso demonstrate that the most frequent mutational event by far (n = 34) involves small reductions in VNTR fragment size (median loss 22 repeat units, range 2‐1.54), furthermore, in one‐half of these cases, this event is biallelic. We wanted to test whether these somatic mutations mirror the same genetic instability as seen by RER (replication error), a phenomenon recently described in tumour DNA from both sporadic and familial cases of CRC. All blood/tumour DNA pairs displaying MS1 mutation (n = 37) as well as 37 randomly selected pairs without MS1 mutation were tested with four tetranucleotide short tandem repeats (STRs, microsatellites). There is a strong association between mutations at the D1S7 locus and the occurrence of new STR alleles (P<0.001). This is the first report of the existence of a minisatellite as a marker for genetic instability/RER in colorectal carcinomas. The findings may also cast light upon the mechanism for somatic mutations in this minisatellite. © 1995 Wiley‐Liss, Inc.