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‣ Functional Analysis of the Neurofibromatosis Type 2 Protein by Means of Disease-Causing Point Mutations

Stokowski, Renee P.; Cox, David R.
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
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Despite intense study of the neurofibromatosis type 2 (NF2) tumor-suppressor protein merlin, the biological properties and tumor-suppressor functions of merlin are still largely unknown. In this study, we examined the molecular activities of NF2-causing mutant merlin proteins in transfected mammalian cells, to elucidate the merlin properties that are critical for tumor-suppressor function. Most important, we found that 80% of the merlin mutants studied significantly altered cell adhesion, causing cells to detach from the substratum. This finding implies a function for merlin in regulating cell-matrix attachment, and changes in cell adhesion caused by mutant protein expression may be an initial step in the pathogenesis of NF2. In addition, five different mutations in merlin caused a significant increase in detergent solubility of merlin compared to wild type, indicating a decreased ability to interact with the cytoskeleton. Although not correlated to the cell-adhesion phenotype, four missense mutations decreased the binding of merlin to the ERM-interacting protein EBP-50, implicating this interaction in merlin inhibition of cell growth. Last, we found that some NF2 point mutations in merlin most closely resembled gain-of-function alleles in their cellular phenotype...

‣ Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly.

Mears, A J; Jordan, T; Mirzayans, F; Dubois, S; Kume, T; Parlee, M; Ritch, R; Koop, B; Kuo, W L; Collins, C; Marshall, J; Gould, D B; Pearce, W; Carlsson, P; Enerbäck, S; Morissette, J; Bhattacharya, S; Hogan, B; Raymond, V; Walter, M A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1998 Português
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Genetic linkage, genome mismatch scanning, and analysis of patients with alterations of chromosome 6 have indicated that a major locus for development of the anterior segment of the eye, IRID1, is located at 6p25. Abnormalities of this locus lead to glaucoma. FKHL7 (also called "FREAC3"), a member of the forkhead/winged-helix transcription-factor family, has also been mapped to 6p25. DNA sequencing of FKHL7 in five IRID1 families and 16 sporadic patients with anterior-segment defects revealed three mutations: a 10-bp deletion predicted to cause a frameshift and premature protein truncation prior to the FKHL7 forkhead DNA-binding domain, as well as two missense mutations of conserved amino acids within the FKHL7 forkhead domain. Mf1, the murine homologue of FKHL7, is expressed in the developing brain, skeletal system, and eye, consistent with FKHL7 having a role in ocular development. However, mutational screening and genetic-linkage analyses excluded FKHL7 from underlying the anterior-segment disorders in two IRID1 families with linkage to 6p25. Our findings demonstrate that, although mutations of FKHL7 result in anterior-segment defects and glaucoma in some patients, it is probable that at least one more locus involved in the regulation of eye development is also located at 6p25.

‣ Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles.

Mendez, M; Sorkin, L; Rossetti, M V; Astrin, K H; del C Batlle, A M; Parera, V E; Aizencang, G; Desnick, R J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1998 Português
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Familial porphyria cutanea tarda (f-PCT) results from the half-normal activity of uroporphyrinogen decarboxylase (URO-D). Heterozygotes for this autosomal dominant trait are predisposed to photosensitive cutaneous lesions by various ecogenic factors, including iron overload and alcohol abuse. The 3.6-kb URO-D gene was completely sequenced, and a long-range PCR method was developed to amplify the entire gene for mutation analysis. Four missense mutations (M165R, L195F, N304K, and R332H), a microinsertion (g10insA), a deletion (g645Delta1053), and a novel exonic splicing defect (E314E) were identified. Expression of the L195F, N304K, and R332H polypeptides revealed significant residual activity, whereas reverse transcription-PCR and sequencing demonstrated that the E314E lesion caused abnormal splicing and exon 9 skipping. Haplotyping indicated that three of the four families with the g10insA mutation were unrelated, indicating that these microinsertions resulted from independent mutational events. Screening of nine f-PCT probands revealed that 44% were heterozygous or homozygous for the common hemochromatosis mutations, which suggests that iron overload may predispose to clinical expression. However, there was no clear correlation between f-PCT disease severity and the URO-D and/or hemochromatosis genotypes. These studies doubled the number of known f-PCT mutations...

‣ Partial Loss-of-Function Mutations in Insulin-Degrading Enzyme that Induce Diabetes also Impair Degradation of Amyloid β-Protein

Farris, Wesley; Mansourian, Stefan; Leissring, Malcolm A.; Eckman, Elizabeth A.; Bertram, Lars; Eckman, Christopher B.; Tanzi, Rudolph E.; Selkoe, Dennis J.
Fonte: American Society for Investigative Pathology Publicador: American Society for Investigative Pathology
Tipo: Artigo de Revista Científica
Publicado em /04/2004 Português
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The causes of cerebral accumulation of amyloid β-protein (Aβ) in most cases of Alzheimer’s disease (AD) remain unknown. We recently found that homozygous deletion of the insulin-degrading enzyme (IDE) gene in mice results in an early and marked elevation of cerebral Aβ. Both genetic linkage and allelic association in the IDE region of chromosome 10 have been reported in families with late-onset AD. For IDE to remain a valid candidate gene for late-onset AD on functional grounds, it must be shown that partial loss of function of IDE can still alter Aβ degradation, but without causing early, severe elevation of brain Aβ. Here, we show that naturally occurring IDE missense mutations in a well-characterized rat model of type 2 diabetes mellitus (DM2) result in decreased catalytic efficiency and a significant ∼15 to 30% deficit in the degradation of both insulin and Aβ. Endogenously secreted Aβ40 and Aβ42 are significantly elevated in primary neuronal cultures from animals with the IDE mutations, but there is no increase in steady-state levels of rodent Aβ in the brain up to age 14 months. We conclude that naturally occurring, partial loss-of-function mutations in IDE sufficient to cause DM2 also impair neuronal regulation of Aβ levels...

‣ Mutations in DJ-1 are rare in familial Parkinson disease

Pankratz, Nathan; Pauciulo, Michael W.; Elsaesser, Veronika E.; Marek, Diane K.; Halter, Cheryl A.; Wojcieszek, Joanne; Rudolph, Alice; Shults, Clifford W.; Foroud, Tatiana; Nichols Ph.D., William C.;
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Mutations in DJ-1 (PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD.

‣ Plexin-B1 mutations in prostate cancer

Wong, Oscar Gee-Wan; Nitkunan, Tharani; Oinuma, Izumi; Zhou, Chun; Blanc, Veronique; Brown, Richard S. D.; Bott, Simon R. J.; Nariculam, Joseph; Box, Gary; Munson, Phillipa; Constantinou, Jason; Feneley, Mark R.; Klocker, Helmut; Eccles, Suzanne A.; Negis
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Semaphorins are a large class of secreted or membrane-associated proteins that act as chemotactic cues for cell movement via their transmembrane receptors, plexins. We hypothesized that the function of the semaphorin signaling pathway in the control of cell migration could be harnessed by cancer cells during invasion and metastasis. We now report 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene. Mutations were found in 89% (8 of 9) of prostate cancer bone metastases, in 41% (7 of 17) of lymph node metastases, and in 46% (41 of 89) of primary cancers. Forty percent of prostate cancers contained the same mutation. Overexpression of the Plexin-B1 protein was found in the majority of primary tumors. The mutations hinder Rac and R-Ras binding and R-RasGAP activity, resulting in an increase in cell motility, invasion, adhesion, and lamellipodia extension. These results identify a key role for Plexin-B1 and the semaphorin signaling pathway it mediates in prostate cancer.

‣ Mutations in the GIGYF2 (TNRC15) Gene at the PARK11 Locus in Familial Parkinson Disease

Lautier, Corinne; Goldwurm, Stefano; Dürr, Alexandra; Giovannone, Barbara; Tsiaras, William G.; Pezzoli, Gianni; Brice, Alexis; Smith, Robert J.
Fonte: American Society of Human Genetics Publicador: American Society of Human Genetics
Tipo: Artigo de Revista Científica
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The genetic basis for association of the PARK11 region of chromosome 2 with familial Parkinson disease (PD) is unknown. This study examined the GIGYF2 (Grb10-Interacting GYF Protein-2) (TNRC15) gene, which contains the PARK11 microsatellite marker with the highest linkage score (D2S206, LOD 5.14). The 27 coding exons of the GIGYF2 gene were sequenced in 123 Italian and 126 French patients with familial PD, plus 131 Italian and 96 French controls. A total of seven different GIGYF2 missense mutations resulting in single amino acid substitutions were present in 12 unrelated PD index patients (4.8%) and not in controls. Three amino acid insertions or deletions were found in four other index patients and absent in controls. Specific exon sequencing showed that these ten sequence changes were absent from a further 91 controls. In four families with amino acid substitutions in which at least one other PD case was available, the GIGYF2 mutations (Asn56Ser, Thr112Ala, and Asp606Glu) segregated with PD. There were, however, two unaffected carriers in one family, suggesting age-dependent or incomplete penetrance. One index case (PD onset age 33) inherited a GIGYF2 mutation (Ile278Val) from her affected father (PD onset age 66) and a previously described PD-linked mutation in the LRRK2 gene (Ile1371Val) from her affected mother (PD onset age 61). The earlier onset and severe clinical course in the index patient suggest additive effects of the GIGYF2 and LRRK2 mutations. These data strongly support GIGYF2 as a PARK11 gene with a causal role in familial PD.

‣ The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations

Zhao, Nianxi; Zhu, Fengxue; Yuan, Fenghua; Haick, Anoria K.; Fukushige, Shinichi; Gu, Liya; Her, Chengtao
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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Our previous studies indicate that hMRE11 plays a role in MMR, and this function of hMRE11 is most likely mediated by the hMLH1-hMRE11 interaction. Here, we explored the functional implications of the hMLH1-hMRE11 interaction in MMR and the effects of hMLH1 mutations on their interaction. Our in vitro MMR assay demonstrated that the dominant-negative hMRE11452–634 mutant peptide (i.e., harboring only the hMLH1-interacting domain) imparted a significant reduction in both 3’ excision and 3’-directed MMR activities. Furthermore, the expression of hMRE11452–634, and to a lesser extent hMRE111–634 (ATLD1), impaired G2/M checkpoint control in response to MNU and cisplatin treatments, rendering cells resistant to killings by these two anticancer drugs. Analysis of 38 hMLH1 missense mutations showed that the majority of mutations caused significant (> 50%) reductions in their interaction with hMRE11, suggesting a potential link between aberrant protein interaction and the pathogenic effects of hMLH1 variants.

‣ Rett Syndrome-causing Mutations in Human MeCP2 Result in Diverse Structural Changes That Impact Folding and DNA Interactions*

Ghosh, Rajarshi P.; Horowitz-Scherer, Rachel A.; Nikitina, Tatiana; Gierasch, Lila M.; Woodcock, Christopher L.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 18/07/2008 Português
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Most cases of Rett syndrome (RTT) are caused by mutations in the methylated DNA-binding protein, MeCP2. Here, we have shown that frequent RTT-causing missense mutations (R106W, R133C, F155S, T158M) located in the methylated DNA-binding domain (MBD) of MeCP2 have profound and diverse effects on its structure, stability, and DNA-binding properties. Fluorescence spectroscopy, which reports on the single tryptophan in the MBD, indicated that this residue is strongly protected from the aqueous environment in the wild type but is more exposed in the R133C and F155S mutations. In the mutant proteins R133C, F155S, and T158M, the thermal stability of the domain was strongly reduced. Thermal stability of the wild-type protein was increased in the presence of unmethylated DNA and was further enhanced by DNA methylation. DNA-induced thermal stability was also seen, but to a lesser extent, in each of the mutant proteins. Circular dichroism (CD) of the MBD revealed differences in the secondary structure of the four mutants. Upon binding to methylated DNA, the wild type showed a subtle but reproducible increase in α-helical structure, whereas the F155S and R106W did not acquire secondary structure with DNA. Each of the mutant proteins studied is unique in terms of the properties of the MBD and the structural changes induced by DNA binding. For each mutation...

‣ Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene

Staples, E R; McDermott, E M; Reiman, A; Byrd, P J; Ritchie, S; Taylor, A M R; Davies, E G
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /08/2008 Português
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Immunodeficiency affects over half of all patients with ataxia telangiectasia (A-T) and when present can contribute significantly to morbidity and mortality. A retrospective review of clinical history, immunological findings, ataxia telangiectasia mutated (ATM) enzyme activity and ATM mutation type was conducted on 80 consecutive patients attending the National Clinic for Ataxia Telangiectasia, Nottingham, UK between 1994 and 2006. The aim was to characterize the immunodeficiency in A-T and determine its relationship to the ATM mutations present. Sixty-one patients had mutations resulting in complete loss of ATM kinase activity (group A) and 19 patients had leaky splice or missense mutations resulting in residual kinase activity (group B). There was a significantly higher proportion of patients with recurrent sinopulmonary infections in group A compared with group B (31 of 61 versus four of 19 P = 0·03) and a greater need for prophylactic antibiotics (30 of 61 versus one of 19 P = 0·001). Comparing group A with group B patients, 25 of 46 had undetectable/low immunoglobulin A (IgA) levels compared with none of 19; T cell lymphopenia was found in 28 of 56 compared with one of 18 and B cell lymphopenia in 35 of 55 compared with four of 18 patients (P = 0·00004...

‣ Molecular pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts: mutations in MLC1 cause folding defects

Duarri, Anna; Teijido, Oscar; López-Hernández, Tania; Scheper, Gert C.; Barriere, Herve; Boor, Ilja; Aguado, Fernando; Zorzano, Antonio; Palacín, Manuel; Martínez, Albert; Lukacs, Gergely L.; van der Knaap, Marjo S.; Nunes, Virginia; Estévez, Raúl
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy, most often caused by mutations in the MLC1 gene. MLC1 is an oligomeric plasma membrane (PM) protein of unknown function expressed mainly in glial cells and neurons. Most disease-causing missense mutations dramatically reduced the total and PM MLC1 expression levels in Xenopus oocytes and mammalian cells. The impaired expression of the mutants was verified in primary cultures of rat astrocytes, as well as human monocytes, cell types that endogenously express MLC1, demonstrating the relevance of the tissue culture models. Using a combination of biochemical, pharmacological and imaging methods, we also demonstrated that increased endoplasmatic reticulum-associated degradation and endo-lysosomal-associated degradation can contribute to the cell surface expression defect of the mutants. Based on these results, we suggest that MLC1 mutations reduce protein levels in vivo. Since the expression defect of the mutants could be rescued by exposing the mutant-protein expressing cells to low temperature and glycerol, a chemical chaperone, we propose that MLC belongs to the class of conformational diseases. Therefore, we suggest the use of pharmacological strategies that improve MLC1 expression to treat MLC patients.

‣ Human CHN1 mutations hyperactivate α2-chimaerin and cause Duane’s retraction syndrome

Miyake, Noriko; Chilton, John; Psatha, Maria; Cheng, Long; Andrews, Caroline; Chan, Wai-Man; Law, Krystal; Crosier, Moira; Lindsay, Susan; Cheung, Michelle; Allen, James; Gutowski, Nick J; Ellard, Sian; Young, Elizabeth; Iannaccone, Alessandro; Appukuttan
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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The RacGAP molecule α2-chimaerin is implicated in neuronal signaling pathways required for precise guidance of developing corticospinal axons. We now demonstrate that a variant of Duane’s retraction syndrome, a congenital eye movement disorder in which affected individuals show aberrant development of axon projections to the extraocular muscles, can result from gain-of-function heterozygous missense mutations in CHN1 that increase α2-chimaerin RacGAP activity in vitro. A subset of mutations enhances α2-chimaerin membrane translocation and/or α2-chimaerin’s previously unrecognized ability to form a complex with itself. In ovo expression of mutant CHN1 alters the development of ocular motor axons. These data demonstrate that human CHN1 mutations can hyperactivate α2-chimaerin and result in aberrant cranial motor neuron development.

‣ Pathogenesis of retinitis pigmentosa associated with apoptosis-inducing mutations in carbonic anhydrase IV

Datta, Rupak; Waheed, Abdul; Bonapace, Giuseppe; Shah, Gul N.; Sly, William S.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Missense mutations in the carbonic anhydrase IV (CA IV) gene have been identified in patients with an autosomal dominant form of retinitis pigmentosa (RP17). We used two transient expression systems to investigate the molecular mechanism by which the newly identified CA IV mutations, R69H and R219S, contribute to retinal pathogenesis. Although the R219S mutation drastically reduced the activity of the enzyme, the R69H mutation had a minimal effect, suggesting that loss of CA activity is not the molecular basis for their pathogenesis. Defective processing was apparent for both mutant proteins. Cell surface-labeling techniques showed that the R69H and R219S mutations both impaired the trafficking of CA IV to the cell surface, resulting in their abnormal intracellular retention. Expression of both CA IV mutants induced elevated levels of the endoplasmic reticulum (ER) stress markers, BiP and CHOP, and led to cell death by apoptosis. They also had a dominant-negative effect on the secretory function of the ER. These properties are similar to those of R14W CA IV, the signal sequence variant found in the original patients with RP17. These findings suggest that toxic gain of function involving ER stress-induced apoptosis is the common mechanism for pathogenesis of this autosomal-dominant disease. Apoptosis induced by the CA IV mutants could be prevented...

‣ Sulfonylurea Receptor 1 Mutations That Cause Opposite Insulin Secretion Defects with Chemical Chaperone Exposure*S⃞

Pratt, Emily B.; Yan, Fei-Fei; Gay, Joel W.; Stanley, Charles A.; Shyng, Show-Ling
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 20/03/2009 Português
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The β-cell ATP-sensitive potassium (KATP) channel composed of sulfonylurea receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability. Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes. Here we report that two hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. Under normal conditions, both mutant channels showed poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital hyperinsulinism patients. This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for KATP channels. The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels...

‣ Novel Mutations in ACVR1 Result in Atypical Features in Two Fibrodysplasia Ossificans Progressiva Patients

Petrie, Kirsten A.; Lee, Wen Hwa; Bullock, Alex N.; Pointon, Jenny J.; Smith, Roger; Russell, R. Graham G.; Brown, Matthew A.; Wordsworth, B. Paul; Triffitt, James T.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 30/03/2009 Português
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Fibrodysplasia Ossificans Progressiva (FOP) is a rare, heritable condition typified by progression of extensive ossification within skeletal muscle, ligament and tendon together with defects in skeletal development. The condition is easily diagnosed by the presence of shortened great toes and there is severe advancement of disability with age. FOP has been shown to result from a point mutation (c.617G>A) in the ACVR1 gene in almost all patients reported. Very recently two other mutations have been described in three FOP patients. We present here evidence for two further unique mutations (c.605G>T and c.983G>A) in this gene in two FOP patients with some atypical digit abnormalities and other clinical features. The observation of disparate missense mutations mapped to the GS and kinase domains of the protein supports the disease model of mild kinase activation and provides a potential rationale for phenotypic variation.

‣ ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation

Le Goff, Carine; Morice-Picard, Fanny; Dagoneau, Nathalie; Wang, Lauren W; Perrot, Claire; Crow, Yanick J; Bauer, Florence; Flori, Elisabeth; Prost-Squarcioni, Catherine; Krakow, Deborah; Ge, Gaoxiang; Greenspan, Daniel S; Bonnet, Damien; Le Merrer, Marti
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/2008 Português
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Geleophysic dysplasia is an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin and cardiac valvular anomalies often responsible for an early death. Studying six geleophysic dysplasia families, we first mapped the underlying gene to chromosome 9q34.2 and identified five distinct nonsense and missense mutations in ADAMTSL2 (a disintegrin and metalloproteinase with thrombospondin repeats–like 2), which encodes a secreted glycoprotein of unknown function. Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to reduced secretion of the mutated proteins, possibly owing to the misfolding of ADAMTSL2. A yeast two-hybrid screen showed that ADAMTSL2 interacts with latent TGF-β–binding protein 1. In addition, we observed a significant increase in total and active TGF-β in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia. These data suggest that ADAMTSL2 mutations may lead to a dysregulation of TGF-β signaling and may be the underlying mechanism of geleophysic dysplasia.

‣ Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions

Cheng, Alan; Zhang, Mei; Okubo, Minoru; Omichi, Kaoru; Saltiel, Alan R.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Glycogen storage disease type III (GSDIII) is a metabolic disorder characterized by a deficiency in the glycogen debranching enzyme, amylo-1,6-glucosidase,4-α-glucanotransferase (AGL). Patients with GSDIII commonly exhibit hypoglycemia, along with variable organ dysfunction of the liver, muscle or heart tissues. The AGL protein binds to glycogen through its C-terminal region, and possesses two separate domains for the transferase and glucosidase activities. Most causative mutations are nonsense, and how they affect the enzyme is not well understood. Here we investigated four rare missense mutations to determine the molecular basis of how they affect AGL function leading to GSDIII. The L620P mutant primarily abolishes transferase activity while the R1147G variant impairs glucosidase function. Interestingly, mutations in the carbohydrate-binding domain (CBD; G1448R and Y1445ins) are more severe in nature, leading to significant loss of all enzymatic activities and carbohydrate binding ability, as well as enhancing targeting for proteasomal degradation. This region (Y1445–G1448R) displays virtual identity across human and bacterial species, suggesting an important role that has been conserved throughout evolution. Our results clearly indicate that inactivation of either enzymatic activity is sufficient to cause GSDIII disease and suggest that the CBD of AGL plays a major role to coordinate its functions and regulation by the ubiquitin–proteasome system.

‣ A MELAS syndrome family harboring two mutations in mitochondrial genome

Choi, Byung-Ok; Hwang, Jung Hee; Kim, Joonki; Cho, Eun Min; Cho, Sun Young; Hwang, Su Jin; Lee, Hyang Woon; Kim, Song Ja; Chung, Ki Wha
Fonte: Korean Society of Medical Biochemistry and Molecular Biology Publicador: Korean Society of Medical Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous mitochondrial disorder with variable clinical symptoms. Here, from the sequencing of the entire mitochondrial genome, we report a Korean MELAS family harboring two homoplasmic missense mutations, which were reported 9957T > C (Phe251Leu) transition mutation in the cytochrome c oxidase subunit 3 (COX3) gene and a novel 13849A > C (Asn505His) transversion mutation in the NADH dehydrogenase subunit 5 (ND5) gene. Neither of these mutations was found in 205 normal controls. Both mutations were identified from the proband and his mother, but not his father. The patients showed cataract symptom in addition to MELAS phenotype. We believe that the 9957T > C mutation is pathogenic, however, the 13849A > C mutation is of unclear significance. It is likely that the 13849A > C mutation might function as the secondary mutation which increase the expressivity of overlapping phenotypes of MELAS and cataract. This study also demonstrates the importance of full sequencing of mtDNA for the molecular genetic understanding of mitochondrial disorders.

‣ Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa

Friedman, James S.; Ray, Joseph W.; Waseem, Naushin; Johnson, Kory; Brooks, Matthew J.; Hugosson, Therése; Breuer, Debra; Branham, Kari E.; Krauth, Daniel S.; Bowne, Sara J.; Sullivan, Lori S.; Ponjavic, Vesna; Gränse, Lotta; Khanna, Ritu; Trager, Edwar
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 12/06/2009 Português
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Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G→A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.

‣ Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation

Puckett, Rebecca L.; Moore, Steven A.; Winder, Thomas L.; Willer, Tobias; Romansky, Stephen G.; Covault, Kelly King; Campbell, Kevin P.; Abdenur, Jose E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
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The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of α-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced α-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of α-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of α-dystroglycan hypoglycosylation in skeletal muscle.