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PubMed1996

Prognosis is correlated with p53 mutation type for soft tissue sarcoma patients.

We investigated the prognostic value of p53 mutation type for 145 soft tissue sarcoma patients. In a PCR-SSCP-sequencing analysis, 15 mutations were identified: 10 non-frameshift (non-fs) and 5 frameshift (fs) mutations. Patients possessing non-fs mutations had a significantly poorer prognosis than patients without p53 mutations (P = 0.014), according to Cox's multivariate analysis. In contrast, the survival of five patients with fs mutations was not affected by their mutation type. Furthermore, occurrence of lymph node metastases and recurrences was correlated with the mutation type; i.e., 4 of 10 and 5 of 10 patients with non-fs mutations showed lymph node metastases and recurrences, respectively, whereas none of the patients with fs mutations showed lymph node metastases and only one a recurrence. Therefore, for the evaluation of prognosis, we suggest applying not the p53 mutational status in general, but the specific type of mutation.

Adult↗
PubMed2006

Intronic mutation in the PGK1 gene may cause recurrent myoglobinuria by aberrant splicing.

A 33-year-old man with mental retardation and recurrent myoglobinuria demonstrated a deficiency in the phosphoglycerate kinase 1 (PGK1) activity of his muscles and erythrocytes. His PGK1 gene had intronic G-to-A substitution 5 nucleotides downstream from the normal exon 7 5' splice site (IVS7 + 5 G>A). This novel mutation results in a frame shift due to the insertion of 52 bp of intron 7 in the mature mRNA by aberrant splicing.

Adult↗
PubMed2006

Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta.

Mutations in the type I collagen genes COL1A1 and COL1A2 are responsible for the dominantly inherited connective tissue disorder osteogenesis imperfecta (OI). The severity of OI is diverse, ranging from perinatal lethality to a very mild phenotype that is characterized by normal stature and the absence of deformities. Although there have been several studies on the mutational spectra of COL1A1 and/or COL1A2 in Western populations, very few cases have been reported from Asia. In this study, we investigated 67 unrelated Korean probands with OI and used nucleotide sequence analysis to detect COL1A1 and COL1A2 mutations. Thirty-five different mutations were identified in the two genes, including 24 novel mutations. Among the 35 kinds of detected mutations, 15 were glycine substitutions (seven in COL1A1 and eight in COL1A2), one was a nonsense mutation, four were frameshift mutations in COL1A1, three were in-frame duplications in COL1A2, and 12 were splice site mutations (seven in COL1A1 and five in COL1A2). Until now, mutations in the COL1A1 and COL1A2 genes known to cause OI were unique and rarely repeated in other families. Interestingly, the c.982G>A (p.Gly328Ser) mutation in COL1A2 was found recurrently and was the causative mutation in five independent OI probands. Haplotype analysis of the COL1A2 gene revealed that four probands from five independent OI probands with c.982G>A (p.Gly328Ser) had a common haplotype. Our clinical data showed the heterogeneity even within a specific genotype, which suggested the complex expression of this disease.

Adolescent↗
PubMed2002

OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease.

Dominant optic atrophy (DOA) is the most common form of inherited optic neuropathy. Although heterogeneous, a major locus has been mapped to chromosome 3q28 and the responsible gene, OPA1, was recently identified. OPA1 is a mitochondrial dynamin-related GTPase implicated in the formation and maintenance of the mitochondrial network. To date, 62 mutations have been identified in a total of 201 DOA patients. Most of them (90%) are distributed from exons 8 to 28 with a majority in the GTPase domain (54%). None were found in the alternatively spliced exons 4, 4b, and 5b. Half of them are truncative mutations (50%) with a frequent recurrent allele, c.2708delTTAG. Most missense mutations (81%) cluster within the putative GTPase domain. Various pathogenic mechanisms may play a role in OPA1 DOA. Truncative mutations in the N-terminal region and perhaps missense mutations in the GTPase domain lead to a loss of function of the encoded protein and haplotype insufficiency. However, there is a cluster of truncation mutations in the in C-terminus, a putative dimerization domain, that could act through a dominant negative effect. The findings that OPA1-type DOA, as Leber optic neuropathy, is caused by the impairment of a mitochondrial protein address the question of the vulnerability of the retinal ganglion cell in response to mitochondrial defects.

Animals↗
PubMed1998

Genetic and molecular definition of complementation group D in MHC class II deficiency.

Four complementation groups, A, B, C and D, have been described among cell lines defective in the coordinate expression of MHC class II genes. These include cell lines established from patients affected with MHC class II deficiency and experimentally generated mutant cell lines. Group D, in contrast to the other groups, was for a long time represented only by the 6.1.6 mutant cell line. The gene responsible for the defect in this group, RFXAP , recently was cloned and found to be mutated in the 6.1.6 cell line and in three patients. Here we report fusion experiments in several new HLA class II-deficient patients, completing the classification of the majority of known patients into the four complementation groups. Patients from five unrelated families were classified in complementation group D, while nine others fall into complementation groups A and B. None of the patients defined a new complementation group. Full correction of MHC class II expression was obtained in cells from patients belonging to group D by transfection with the RFXAP cDNA. The RFXAP coding region was found to be mutated in all patients. Mutations were found to be recurrent since only three different mutations have been found in the eight unrelated families reported to date.

Antigens, Differentiation, B-Lymphocyte↗
PubMedDate not supplied

Severe protein S deficiency associated with heterozygous factor V Leiden mutation in a child with purpura fulminans.

Homozygous or compound heterozygous protein S (PS) deficiency is very rare in the population; only 8 patients from 6 different families have been reported. On the other hand, the factor V Leiden (FVL) mutation is a frequent cause of inherited prothrombotic disorder. Here the authors report a case of patient with severe PS deficiency associated with the FVL mutation who has had purpura fulminans since the age of 10 days. She is the first child of a consanguineous marriage. Her father is double heterozygous for PS deficiency and FVL mutation and has recurrent thrombosis. This is the first case of severe PS deficiency combined with the FVL mutation. This suggests the need for complete evaluation of patients with purpura fulminans for thrombotic factors.

Factor V↗
PubMed2004

Leukaemia inhibitory factor (LIF) gene mutations in women with unexplained infertility and recurrent failure of implantation after IVF and embryo transfer.

OBJECTIVE: Leukaemia inhibitory factor (LIF) plays a central role in the control of implantation. We undertook this study to investigate the prevalence of LIF gene alterations in women with unexplained infertility and with recurrent failure of implantation after in vitro fertilisation (IVF) and embryo transfer. PATIENTS AND METHODS: Forty five women with recurrent failure of implantation after IVF (group A), 50 with unexplained infertility (group B) and 105 fertile women (controls) were screened for LIF gene mutations. Standard genomic DNA extraction, PCR amplification of the LIF gene and single-strand conformation polymorphism (SSCP) analysis were used to search for mutations which were subsequently confirmed by DNA sequencing. RESULTS: In group A, one woman was identified as having a neutral LIF gene polymorphism in exon 3 without affecting protein conformation. In group B, one woman with a heterozygous mutation and one with a neutral polymorphism were detected. In controls, only one woman with a neutral polymorphism in the intron between exons 2 and 3 was found. The woman with a potentially functional LIF gene mutation in group B achieved an ongoing clinical pregnancy after ovarian superovulation. DISCUSSION: Potentially functional mutations in the LIF gene do infrequently occur in women with unexplained infertility and may play a role in the etiology of infertility. However, routine screening for LIF mutations or polymorphisms in these women is not justified for the low prevalence of gene alterations.

Abortion, Habitual↗
PubMed2003

Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation.

BACKGROUND: X-linked hereditary demyelinating neuropathies (Charcot-Marie-Tooth Disease [CMTX]) caused by mutations in the connexin 32 (Cx32) gene account for approximately 10% to 20% of all hereditary demyelinating neuropathies. Mild subclinical central nervous system (CNS) involvement has been previously described, and CMTX patients with transient white matter lesions allied to CNS symptoms have very recently been described. This is of potential interest, as Cx32 is widely expressed in both peripheral nerve and the brain. PATIENTS: We describe a family with hereditary demyelinating neuropathy and transient CNS symptoms. For this study, family members underwent genotyping and detailed clinical, electrophysiological, and magnetic resonance imaging examination. RESULTS: We present a CMTX family with a novel mutation in the Cx32 gene. Affected family members show, in addition to the classic polyneuropathy, transient and reversible white matter lesions on magnetic resonance imaging scans, correlating similarly transient CNS symptoms. CONCLUSION: Patients with CMTX can present with transient CNS symptoms and marked white matter lesions on magnetic resonance imaging scans.

Adult↗
PubMed2005

Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy.

BRCA1 and BRCA2 germline mutations are associated with a strong risk of breast cancer, which may preclude breast-conserving treatment in carriers. This study examined whether mutation status influenced the rate of breast cancer recurrence following breast-conserving treatment. BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer, who had been treated with breast-conserving surgery and radiotherapy. The 131 patients with familial history were matched to 261 patients without, according to age at diagnosis and year of treatment. The follow-up of controls was at least equal to the time-interval between diagnosis and genetic testing in familial cases. Matched cohorts were compared according to rates of breast cancer recurrence as first event and contralateral breast cancer using log-rank tests. BRCA1/2 mutations were found in 20.6% patients with a family history. Nineteen patients had a BRCA1 mutation and 8 had a BRCA2 mutation. Breast cancers in mutation carriers were more often grade III (p<10-4) and oestrogen receptor negative (p=0.005) than tumours in both non-carriers and controls. Median follow-up for all 392 patients was 8.75 years. No significant differences in breast cancer recurrence as first event were seen between BRCA1/2 tumours and controls (p=0.47), carriers and non-carriers with a family history (p=0.96), or non-carriers and controls (p=0.10). On multivariate analysis, age was the most important factor significantly predicting for breast cancer recurrence. The rate of contralateral breast cancer was significantly increased in all patients with a family history: BRCA1/2 carriers versus controls (p=0.0003), non-carriers versus controls (p=0.0034) and carriers versus non-carriers (p=0.02). At a 9-year median follow-up, the rate of ipsilateral breast cancer recurrence was not higher in BRCA1 and BRCA2 mutation carriers than in non-carriers with a family history or sporadic cases. These results support the hypothesis that breast tumours in BRCA carriers are more sensitive to radiation. Therefore, breast-conserving treatment can be offered to these patients. However, longer follow-up is needed to ensure that the rate of new primary cancer in the treated breast does not increase in the long-term.

Adult↗
PubMed2003

Is recurrent venous thromboembolism more frequent in homozygous patients for the factor V Leiden mutation than in heterozygous patients?

Whether the factor V Leiden mutation increases the risk of recurrent venous thromboembolism (VTE) remains controversial, and homozygous carriers have not been extensively evaluated. In the present cohort study, we have assessed the incidence of recurrent VTE in a subset of non-treated patients previously included in the Procare Register who suffered a first objectively diagnosed VTE. We compared the incidence rates in homozygotes (n = 32) and heterozygotes (n = 108). The median observation time was 4.5 years (range 1.0-6.9 years) in the homozygous group, and 4.15 years (range 0.3-5.9 years) in the heterozygous group. The incidence of recurrence was 5.75/100 patient-years (95% confidence interval = 4.9-7.4) and 3.2/100 patient-years (95% confidence interval = 2.9-3.5) for the homozygotes and heterozygotes, respectively. Homozygotes had a higher overall risk of recurrence than did heterozygotes (relative risk, 1.8; 95% confidence interval = 1.0-6.17). Since short-term prophylaxis was encouraged in risk situations, idiopathic VTE (76%) occurred more frequently than provoked VTE (24%). The precipitating condition was pregnancy in all cases (three homozygotes, one heterozygote). None were receiving prophylaxis. Balancing the risk of recurrence against the risk of major bleeding from oral anticoagulation therapy, it appears that factor V Leiden homozygotes with a first VTE are unlikely to benefit from long-term full-dose oral anticoagulant treatment. All these patients should receive short-term prophylaxis during risk situations, particularly during pregnancy.

Adolescent↗
PubMed2002

Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis.

OBJECTIVE: Familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS) are dominantly inherited autoinflammatory disorders that cause rashes, fever, arthralgia, and in some subjects, AA amyloidosis, and have been mapped to chromosome 1q44. Sensorineural deafness in MWS, and provocation of symptoms by cold in FCU, are distinctive features. This study was undertaken to characterize the genetic basis of FCU, MWS, and an overlapping disorder in French Canadian, British, and Indian families, respectively. METHODS: Mutations in the candidate gene NALP3, which has also been named CIAS1 and PYPAF1, were sought in the study families, in a British/Spanish patient with apparent sporadic MWS, and in matched population controls. Identified variants were sought in 50 European subjects with uncharacterized, apparently sporadic periodic fever syndromes, 48 subjects with rheumatoid arthritis (RA), and 19 subjects with juvenile idiopathic arthritis (JIA). RESULTS: Point mutations, encoding putative protein variants R262W and L307P, were present in all affected members of the Indian and French Canadian families, respectively, but not in controls. The R262W variant was also present in the subject with sporadic MWS. The V200M variant was present in all affected members of the British family with MWS, in 2 of the 50 subjects with uncharacterized periodic fevers, and in 1 of 130 Caucasian and 2 of 48 Indian healthy controls. No mutations were identified among the subjects with RA or JIA. CONCLUSION: These findings confirm that mutations in the NALP3/CIAS1/PYPAF1 gene are associated with FCU and MWS, and that disease severity and clinical features may differ substantially within and between families. Analysis of this gene will improve classification of patients with inherited or apparently sporadic periodic fever syndromes.

Adult↗
PubMed2006

Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation.

A male child initially presented with atypical hemolytic uremic syndrome (HUS) at the age of 4 months and progressed within weeks to end stage renal disease (ESRD). At the age of 2 years he received a live-related kidney transplant from his mother, which, despite initial good function, was lost to recurrent disease after 2 weeks. Complement factor H analysis showed low serum levels and the presence of two mutations on different alleles (c.2918G > A, Cys973Tyr and c.3590T > C, Val1197Ala). His survival on dialysis was at risk because of access failure and recurrent bacteremic episodes. Therefore, at the age of 5 years he received a combined liver-kidney transplant with pre-operative plasma exchange. Initial function of both grafts was excellent and this has been maintained for over 2 years. This report suggests that despite setbacks in previous experience, combined liver-kidney transplantation offers the prospect of a favorable long-term outcome for patients with HUS associated with complement factor H mutations.

Child, Preschool↗
PubMed2005

MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever.

Autosomal recessive autoinflammatory disorder caused by mutations of the mevalonate kinase gene (MVK), leading to mild, incomplete MK enzyme deficiency (MKD), has been known so far as Hyper-IgD and periodic fever syndrome (HIDS) and regarded as mostly occurring in Northern Europe. Here we report the results of the molecular characterization of the first Italian series of patients affected with autoinflammatory disorders and periodic fever. A total of 13 different mutations, scattered throughout the MVK coding region, were identified in either homozygous or compound heterozygous state in 15 patients. The mutation leading to the V377I amino-acid change, already described also in other series, resulted the most common with a frequency of 50% of all MKD alleles. Among the other mutations, eight had never been described before, including an interstitial deletion of 19 nucleotides in exon 2. In addition to these nucleotide changes, private and polymorphic MVK variants have been detected in the patients under analysis and checked also in a set of control individuals. Clinical features are reported for each of the 15 MKD patients, and life-threatening infections and systemic amyloidosis presented as unexpected MKD-related complications. Our study demonstrates that MKD is a common cause of recurrent fever also in the Italian population, where it is associated with both a wide spectrum of previously unreported MVK mutations and peculiar phenotypic features.

Adolescent↗
PubMed2005

The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia.

Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML)/atypical chronic myelogenous leukemia (aCML), myelodysplastic syndrome (MDS), B-lineage acute lymphoblastic leukemia (ALL), T-cell ALL, and chronic lymphocytic leukemia (CLL). Analysis of 222 patients with AML identified JAK2V617F mutations in 4 patients with AML, 3 of whom had a preceding MPD. JAK2V617F mutations were identified in 9 (7.8%) of 116 CMML/a CML samples, and in 2 (4.2%) of 48 MDS samples. We did not identify the JAK2V617F disease allele in B-lineage ALL (n = 83), T-cell ALL (n = 93), or CLL (n = 45). These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in lymphoid malignancies.

Aged↗
PubMed2001

R116C mutation of cationic trypsinogen in a Turkish family with recurrent pancreatitis illustrates genetic microheterogeneity of hereditary pancreatitis.

Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC-->CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.

Adult↗
PubMed2001

[Frequency of antiphospholipid antibodies and Leiden mutation of hemostasis Factor V in unexplained recurrent fetal and embryo loss].

Object of the study are women with a history of unexplained recurrent embryo, fetal and early neonatal death, severe preeclampsia, fetal growth retardation, abruptio placentae, puerperal thromboses. Quite often placental insufficiency is linked to abnormal vascular system and hemostatic disturbancies. In about 65% of the women with a complicated and in 18% of the women with a normal pregnancy are observed different genetic anomalies that lead to a hypercoagulative state. A major place is taken by the Leiden mutation of hemostasis factor V, by protein C and protein S deficiency, etc. Another disease that leads to arterial and venous thromboses and is most often linked to recurrent miscarriage is the antiphospholipid syndrome. Many authors confirm the findings of large placental infarctions and thromboses in women who are positive for antophospholipid antibodies.

Abortion, Habitual↗
PubMed2005

CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia.

Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.

Alleles↗