journal article
Open Access Collection
Home
Saha, Bidisha; Lessel, Davor; Nampoothiri, Sheela; Rao, Anuradha S.; Hisama, Fuki M.; Peter, Dincy; Bennett, Chris; Nürnberg, Gudrun; Nürnberg, Peter; Martin, George M.; Kubisch, Christian; Oshima, Junko
doi: 10.1002/mgg3.1pmid: 23936869
Werner syndrome (WS) is a rare autosomal recessive disorder characterized by multiple features consistent with accelerated aging. It is caused by mutations in the WRN gene, which encodes a RecQ type helicase. To date, more than 70 disease‐causing mutations have been reported. While founder mutations and a corresponding relatively high incidence of WS have been reported in Japan and Sardinia, such mutations have not been previously described among patients of South Asian descent. Here, we report two novel WRN mutations in three pedigrees. A homozygous c.561A>G mutation in exon 6 was identified both in a pedigree from Kerala, India and in a British patient of Pakistani ancestry. Although c.561A>G does not alter the corresponding amino acid (p.Lys187), it creates a cryptic splice site resulting in a 98 bp deletion at the mRNA level (r.557_654del98) followed by a frameshift (p.Lys187Trpfs*13). These two cases shared the same haplotype across the WRN gene, and were distinct from another Indian Werner patient with a homozygous stop codon mutation, c.2855 C > A (p.Ser952*), in exon 24. As the Indian population increases and the awareness of WS grows, we anticipate that more cases will be identified with these founder mutations among South Asian WS patients.
Gerth‐Kahlert, Christina; Williamson, Kathleen; Ansari, Morad; Rainger, Jacqueline K.; Hingst, Volker; Zimmermann, Theodor; Tech, Stefani; Guthoff, Rudolf F.; Heyningen, Veronica; FitzPatrick, David R.
doi: 10.1002/mgg3.2pmid: 24498598
Clinical evaluation and mutation analysis was performed in 51 consecutive probands with severe eye malformations – anophthalmia and/or severe microphthalmia – seen in a single specialist ophthalmology center. The mutation analysis consisted of bidirectional sequencing of the coding regions of SOX2, OTX2, PAX6 (paired domain), STRA6, BMP4, SMOC1, FOXE3, and RAX, and genome‐wide array‐based copy number assessment. Fifteen (29.4%) of the 51 probands had likely causative mutations affecting SOX2 (9/51), OTX2 (5/51), and STRA6 (1/51). Of the cases with bilateral anophthalmia, 9/12 (75%) were found to be mutation positive. Three of these mutations were large genomic deletions encompassing SOX2 (one case) or OTX2 (two cases). Familial inheritance of three intragenic, plausibly pathogenic, and heterozygous mutations was observed. An unaffected carrier parent of an affected child with an identified OTX2 mutation confirmed the previously reported nonpenetrance for this disorder. Two families with SOX2 mutations demonstrated a parent and child both with significant but highly variable eye malformations. Heterozygous loss‐of‐function mutations in SOX2 and OTX2 are the most common genetic pathology associated with severe eye malformations and bi‐allelic loss‐of‐function in STRA6 is confirmed as an emerging cause of nonsyndromal eye malformations.
Andreotti, Giuseppina; Pedone, Emilia; Giordano, Assunta; Cubellis, Maria Vittoria
doi: 10.1002/mgg3.3pmid: 24498599
Phosphomannomutase 2 (PMM2) deficiency represents the most frequent type of congenital disorders of glycosylation. For this disease there is no cure at present. The complete loss of phosphomannomutase activity is probably not compatible with life and people affected carry at least one allele with residual activity. We characterized wild‐type PMM2 and its most common hypomorphic mutant, p.F119L, which is associated with a severe phenotype of the disease. We demonstrated that active species is the dimeric enzyme and that the mutation weakens the quaternary structure and, at the same time, affects the activity and the stability of the enzyme. We demonstrated that ligand binding stabilizes both proteins, wild‐type and F119L‐PMM2, and promotes subunit association in vitro. The strongest effects are observed with glucose‐1,6‐bisphosphate (Glc‐1,6‐P2) or with monophosphate glucose in the presence of vanadate. This finding offers a new approach for the treatment of PMM2 deficiency. We propose to enhance Glc‐1,6‐P2 concentration either acting on the metabolic pathways that control its synthesis and degradation or exploiting prodrugs that are able to cross membranes.
Shibata, Kyoko; Hozawa, Atsushi; Tamiya, Gen; Ueki, Masao; Nakamura, Tomohiro; Narimatsu, Hiroto; Kubota, Isao; Ueno, Yoshiyuki; Kato, Takeo; Yamashita, Hidetoshi; Fukao, Akira; Kayama, Takamasa; Kayama, Takamasa
doi: 10.1002/mgg3.4pmid: 24498600
The impact of cryptic relatedness (CR) on genomic association studies is well studied and known to inflate false‐positive rates as reported by several groups. In contrast, conventional epidemiological studies for environmental risks, the confounding effect of CR is still uninvestigated. In this study, we investigated the confounding effect of unadjusted CR among a rural cohort in the relationship between environmental risk factors (body mass index, smoking status, alcohol consumption) and systolic blood pressure. We applied the methods of population‐based whole‐genome association studies for the analysis of the genome‐wide single nucleotide polymorphism data in 1622 subjects, and detected 20.2% CR in this cohort population. In the case of the sample size, approximately 1000, the ratio of CR to the population was 20.2%, the population prevalence 25%, the prevalence in the CR 26%, heritability for liability 14.3% and prevalence in the subpopulation without CR 26%, the difference of estimated regression coefficient between samples with and without CR was not significant (P‐value = 0.55). On the other hand, in another case with approximately >20% heritability for liability, we showed that confounding due to CR biased the estimation of exposure effects.
Hagen, Christian M.; Aidt, Frederik H.; Havndrup, Ole; Hedley, Paula L.; Jespersgaard, Cathrine; Jensen, Morten; Kanters, Jørgen K.; Moolman‐Smook, Johanna C.; Møller, Daniel V.; Bundgaard, Henning; Christiansen, Michael
doi: 10.1002/mgg3.5pmid: 24498601
Mitochondrial dysfunction is a characteristic of heart failure. Mutations in mitochondrial DNA, particularly in MT‐CYB coding for cytochrome B in complex III (CIII), have been associated with isolated hypertrophic cardiomyopathy (HCM). We hypothesized that MT‐CYB mutations might play an important causal or modifying role in HCM. The MT‐CYB gene was sequenced from DNA isolated from blood from 91 Danish HCM probands. Nonsynonymous variants were analyzed by bioinformatics, molecular modeling and simulation. Two germline‐inherited, putative disease‐causing, nonsynonymous variants: m.15024G>A; p.C93Y and m.15482T>C; p.S246P were identified. Modeling showed that the p.C93Y mutation leads to disruption of the tertiary structure of Cytb by helix displacement, interfering with protein–heme interaction. The p.S246P mutation induces a diproline structure, which alters local secondary structure and induces a kink in the protein backbone, interfering with macromolecular interactions. These molecular effects are compatible with a leaky phenotype, that is, limited but progressive mitochondrial dysfunction. In conclusion, we find that rare, putative leaky mtDNA variants in MT‐CYB can be identified in a cohort of HCM patients. We propose that further patients with HCM should be examined for mutations in MT‐CYB in order to clarify the role of these variants.
Showing 1 to 8 of 8 Articles