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PubMed2004

Not all amino acid substitutions of the common cluster E6 mutation in CYP21 cause congenital adrenal hyperplasia.

More than 90% of all cases of congenital adrenal hyperplasia result from steroid 21-hydroxylase (CYP21) gene mutations. Around 95% of these are either gene deletions or any of nine sequence aberrations that have been transferred from the nearby pseudogene through apparent gene conversions. One such recurrent pseudogene-derived mutation is Cluster E6, a combination of three amino acid substitutions in exon 6: I236N, V237E, and M239K. Cluster E6 is associated with the most severe, salt-wasting form of congenital adrenal hyperplasia. We studied the functional consequences of each missense mutation individually as well as the combined effect of the three mutations comprising Cluster E6. V237E abolished enzyme function and is thus a null mutation, whereas very low but measurable activity remained for I236N. M239K, on the other hand, had no effect on enzyme activity and consequently does not contribute to the disease. Although no allele has been reported yet to contain only one or two missense mutations of Cluster E6, it is a well-known feature of CYP21 that it can harbor many different combinations of pseudogene-derived mutations. The exclusion of M239K as a disease-causing mutation is thus relevant when designing protocols for genetic diagnostics.

Adrenal Hyperplasia, Congenital↗
PubMed2005

Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).

BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. METHODS: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. RESULTS: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. CONCLUSIONS: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.

Adult↗
PubMed2007

[The mutation 35delG of the gene of the connexin 26 is a frequent cause of autosomal-recessive non-syndromic hearing loss in Morocco].

UNLABELLED: Mutations of the connexin 26 gene, GJB2, are the most common cause of non syndromic autosomal-recessive hearing loss. One of the GJB2 mutations, the 35delG, is recurrent in European and Mediterranean populations with allelic frequency of at least 70% in patients with hearing loss caused by GJB2 impairment. OBJECTIVES: To determine the prevalence of the 35delG mutation in non-syndromic autosomal-recessive deafness in Morocco. PATIENTS AND METHODS: We looked for the 35delG mutation among 25 non-related Moroccan children suffering from an autosomal recessive hearing loss. A screening for GJB2 mutations, and then a search for GJB6 deletions were carried out among patients who do not bear the 35delG. RESULTS: Twelve patients were homozygous for the 35delG mutation. This mutation was responsible for almost half of the hearing loss among our patients (48%). There was no other GJB2 or GJB6 mutation among 13 patients. CONCLUSION: This study underlines the advantages of a systematic search for this mutation among deaf children when environmental causes are considered irrelevant. The identification of this genetic anomaly signs the etiologic diagnosis of deafness, which allows a relevant genetic advice, and a better treatment of patients.

Adolescent↗
PubMedDate not supplied

[BRAF initiating mutations in the papillary thyroid carcinoma].

Among genetic alterations most important for the initiation of papillary thyroid carcinoma (PTC) is mutation T1799A in the BRAF gene which is the most frequent event (54.5%) in this type of thyroid cancer. It is seen in all stages, from microcarcinoma through clinically overt disease to anaplastic cancer. It has been shown that BRAF mutation is correlated with PTC histotype. It is identified most frequently in classical PTC and in tall cell variant. Moreover, BRAF mutation is described more often in older patients, whereas in young patients RET/PTC rearrangements dominate. In PTC cases with BRAF mutation V600E the prognosis is poorer, with more cancer invasiveness, metastasis and recurrence. The presence of BRAF mutation is related to the specific gene expression signature, different than in cancer cases showing RET/PTC rearrangement or no known initiating mutation.

Age Factors↗
PubMed1998

Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy.

We analyzed the clinical phenotype and determined the recurrence risks to relatives of patients with T14484C Leber's hereditary optic neuropathy (LHON). LHON is a maternally inherited optic neuropathy that primarily affects adolescent males. It is usually associated with one of three mtDNA mutations: G3460A, G11778A, or T14484C. Definition of recurrence risks for the T14484C mutation previously has not been possible due to the relative scarcity of families with this mutation. We obtained blood samples from index patients and their consenting family members, all of whom were of French Canadian ancestry and screened for LHON mutations in mtDNA. Referring ophthalmologists furnished clinical summaries and patients provided pedigree data. T14484C was the most common mutation in the pedigrees analyzed and was always homoplasmic. In these pedigrees, the ratio of affected males to females was 8:1. Median age at onset for males was 19 years (95th percentile, 40.8 years; range, 6 to 48 years). Some improvement of vision was observed in 58% of patients. Recurrence risks to brothers were 28%, sisters 5%, nephews 30%, nieces 3%, male matrilineal first cousins 19%, and female matrilineal first cousins 4%. Recurrence risks to brothers and nephews were not different; however, recurrence risks to brothers and male cousins and to nephews and male cousins were significantly different. There were no differences in recurrence risks to sisters and nieces or to either group compared with their female cousins. Affected females did not have more affected children than unaffected females. The clinical characteristics of French Canadian patients with T14484C LHON were strikingly similar to those in previous reports, suggesting that recurrence risks are generalizable to other T14484C LHON populations for genetic counseling of T14484C LHON families.

Adolescent↗
PubMed2000

Genetic analysis of Tp53 from urine sediment as a tool for diagnosing recurrence and residual of bladder carcinoma.

OBJECTIVES: Longitudinal study of Tp53 mutation in urine sediments of 26 patients with mutated primary transitional cell carcinoma (TCC) of the urinary bladder at different time periods after transurethral resection of the bladder (TURB), i.e. before and after the first TURB, prior to the control resection and before treatment of a recurrence. METHODS: DNA of the critical Tp53 exons 5-8 was anaylzed by temperature gradients (TGGE) and sequence. RESULTS: (1) In 11 of 12 patients (91.7%) mutation reoccurred with the detection of recurrence of the disease. The mutation frequency in patients without any recurrence was 1 in 8 (12.5%) after a follow-up period of 4-16 months. (2) In 7 of 10 patients, the mutation was no longer detectable in the urine sediment after TURB. (3) The mutation frequency at the control resection 6 weeks after the first TURB was 5 in 7 (71.4%) in patients found to have residual and 1 in 7 (14.2%) in the tumor-free patients. (4) In 9 of 10 samples identical mutations were found by sequence in the recurrent tumor. These results show a significant correlation between the detection of a Tp53 mutation in the urine sediments and tumor recurrence or residual. CONCLUSIONS: (1) Tp53 mutations in the urine sediment could be a useful indicator of tumor recurrence or tumor residual in patients ( approximately 40%) with primary mutated bladder cancer tissue. (2) These results support the monoclonal seeding theory. (3) The finding of identical mutations at different times indicate that the tumor was never totally removed.

Adult↗
PubMed2006

Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma.

Stathmin, a major microtubule-depolymerizing protein, is involved in cell cycle progression and cell motility. This study aimed to elucidate its role in the progression, early tumour recurrence (ETR), and prognosis of hepatocellular carcinoma (HCC). Stathmin mRNA was overexpressed in 88/156 (56%) resected, unifocal, primary HCCs, while p53 mutation was present in 72 (46%) and osteopontin mRNA overexpression in 79 (51%). Stathmin mRNA expression exhibited high concordance (93%) with protein expression in 107 cases examined by immunohistochemistry. Stathmin overexpression correlated with high alpha-fetoprotein (>200 ng/ml, p = 0.02), larger tumour size (>5 cm, p = 0.012), high tumour grade (p < 0.0002), high tumour stage (stage IIIA-IV) with vascular invasion and various degrees of intrahepatic metastasis (p < 1 x 10(-8)), ETR (p = 0.003), and lower 5-year survival (p = 0.0007). Stathmin protein expression was often more intense in the peripheral regions of tumour trabeculae, tumour borders, and portal vein tumour thrombi. Stathmin overexpression correlated with p53 mutation (p = 0.017) and osteopontin overexpression (p = 1 x 10(-8)), both of which were associated with vascular invasion (both p < 0.0001) and poorer prognosis (p < 0.0004 and p = 0.0004, respectively). Regardless of the status of p53 mutation or osteopontin expression, stathmin overexpression was associated with higher vascular invasion (all p < 0.0001). Approximately 90% of HCCs harbouring stathmin overexpression with concomitant p53 mutation or osteopontin overexpression exhibited vascular invasion, and hence the lowest 5-year survival, p = 0.00018 and p = 0.0009, respectively. However, we did not find that stathmin overexpression exerted prognostic impact independent of tumour stage. In conclusion, stathmin expression correlates with metastatic potential, is an important prognostic factor for HCC, and may serve as a useful marker to predict ETR.

Biomarkers, Tumor↗
PubMed1997

Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency.

Deficient arylsulfatase A activity causes the neurodegenerative disease metachromatic leukodystrophy. However, some individuals with deficient enzyme activity appear clinically normal. This "pseudodeficiency" allele commonly found among many reported populations (frequency approximately 0.10) is associated with two A-->G transitions in cis in the arylsulfatase A gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, we studied 400 individuals in the African, European, Indian and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varied from 0.01 in Indians, 0.06 in Europeans, 0.21 in East Asians to 0.32 in Africans. The frequencies of both mutations occurring together ranged from almost non-existent in the Africans and East Asians, to 0.075 in the Europeans and 0.125 in the Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and eight multi-generation families with six polymorphic enzymes showed that, of the five haplotypes found in the general population, only one was linked to the double mutations. Alleles among the four populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans whose alleles were discordant. These results are consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among the Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa at approximately 100,000-200,000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages.

Canada↗
PubMed2000

Chronic clinical course of two patients with severe corneal dystrophy caused by homozygous R124H mutations in the betaig-h3 gene.

PURPOSE: To report the chronic clinical course of two patients with homozygous R124H mutations in the betaig-h3 gene. METHODS: Case reports. RESULTS: Two patients with homozygous R124H mutations in the betaig-h3 gene developed severe juvenile corneal opacities that required keratoplasty. After surgery, corneal opacities recurred and limited the recovery of visual acuity in the chronic follow-up. CONCLUSION: In patients with homozygous R124H mutations in the betaig-h3 gene, recurrence of corneal opacities after keratoplasty limits the recovery of visual acuity in the chronic follow-up.

Child↗
PubMed1997

K-ras mutations and prognosis in large-bowel carcinomas.

BACKGROUND: Colorectal carcinogenesis is regarded as a multistep process involving several genetic alterations, with mutation in the K-ras gene in about half of the tumours. We aimed at clarifying the role of this genetic alteration related to survival and clinicopathologic variables. METHODS: One hundred large-bowel carcinomas operated on between 1978 and 1982 were studied for the presence of point mutations in codons 12 and 13 of the K-ras gene, using enriched polymerase chain reaction amplification, restriction fragment length polymorphism analysis, and direct sequencing. RESULTS: Forty mutations were found (40%): 31 in codon 12 and 9 in codon 13, 7 different types. There was no relationship between tumours with and without K-ras mutations with regard to Dukes' stages, age or sex of the patient, tumour localization, histologic grade, DNA ploidy pattern, HLA-DR staining pattern, or survival. Samples from 5 different localizations in 7 carcinomas showed identical K-ras mutation pattern, as did 19 recurrences/ metastases originating from 11 carcinomas. CONCLUSIONS: When present, the primary tumour shows homogeneous distribution of K-ras mutation, and the mutation follows the carcinoma in the secondary deposit, regardless of lymphogenous or hematogenous spread. The presence of K-ras mutation does not seem to have prognostic significance for the patient, and the precise nucleotide change is furthermore not predictive of tumour behaviour.

Adult↗
PubMedDate not supplied

TP53 mutations in human meningiomas.

Overexpression of p53 has been reported to play a role in the development of neoplasms of the central nervous system. Meningiomas are generally benign intracranial tumors originating from the meninges. Overexpression of the p53 protein in meningiomas and an association with histological type and recurrence has been reported. Mutation of the TP53 gene leads to a more stable p53 protein in quantities high enough for detection by immunohistochemistry. In the search for these mutations the core domain of the TP53 gene of meningiomas has been analyzed. Only a very low incidence of mutations was reported. The apparent discordance between overexpression of p53 protein and TP53 gene mutations may be explained by mutations located outside the core domain. This issue was addressed in the present study. All 11 exons of 17 meningiomas were analyzed for DNA alterations by PCR single-strand conformation polymorphism (PCR-SSCP) analysis with subsequent sequencing. PCR-SSCP analysis showed a various number of band shifts and nucleotide alterations, caused either by alterations in the flanking introns or common polymorphisms (codon 36 and 72). The allele frequencies of the polymorphisms found in this small population of tumors resemble the frequencies reported in the literature. In addition, three nucleotide changes located in introns 2, 3 and 7 were found in 11, 3 and 4, respectively, of 17 specimens. Based on this study and on reports by others we conclude that it is not very likely that TP53 mutations are involved in the etiology of meningiomas.

Adult↗
PubMed2003

Grouping of Y-STR haplotypes discloses European geographic clines.

Y-STR haplotypes are widely studied in Europe and an extensive databasing effort has been conducted (http://www.ystr.org). The distribution of these haplotypes has been considered to present no evidence for substructure at central and southern European level. This picture contrasts with the one that results from Y haplogroups defined by binary markers. This paradox has been solved by admitting that the high STR mutation rate and corresponding recurrence has erased geographic structuration. This explanation prompted us to reanalyse Y-STR haplotypes distribution bearing in mind the commonly admitted model for the generation of diversity in these markers, namely the stepwise mutation model (SMM) and, thus, taking the molecular distance between haplotypes into consideration. Accordingly, we have studied the European distribution of the two most frequent haplotypes in the Iberian Peninsula and their one step neighbours using the European samples deposited in the Y STR database (http://www.ystr.org). For the first group we found a clear-cut decreasing W-E gradient, while for the second the highest frequencies were found in the Iberian Peninsula (3.98% in Portugal and 3.85% in Spain), dropping to 2.88% in France and showing a less well defined SW-NW gradient. Furthermore, we have tested the agreement between haplotype groups and binary markers haplogroups in a random sample of 292 individuals from Northern Portugal. Our results demonstrate that (a) Y-STR haplotype data can be used for wide-scale anthropological approaches disclosing information that has been considered only available through binary markers and (b) forensic use of continental databases needs careful refinement, due to the macro-geographic pattern now evidenced.

Chromosomes, Human, Y↗
PubMed2003

[Peripheral blood mutated p53 DNA and its clinical value in human breast cancer].

OBJECTIVE: To evaluate the clinical value of mutated p53 in the peripheral blood of breast cancer patients. METHODS: Plasma DNA of 126 breast cancer patients and 92 healthy women was examined. DNA extraction from the tumor and tissue samples was performed by a nonorganic method. Plasma DNA was purified on Qiagen columns. PCR-SSCP analysis was performed to examine the point mutations in the conserved exons 5, 6, 7 and 8 of TP53. RESULTS: The mean concentration of plasma DNA was 21 ng/ml in healthy women and 211 ng/ml in patients with breast cancer (P < 0.01). p53 mutations in the primary tumor were detected in 46 of 126 (36.5%) breast cancer patients. Of these 46 patients, 30 (65.1%) were also found to have p53 mutations in their plasma DNA. p53 mutation in plasma DNA was closely correlated with clinical stage, tumor size, lymph node (LN) metastasis and estrogen receptor status (P < 0.05). Survival of the patients with both primary tumor and plasma p53 mutations was the worst. Thirteen of the 22 (59.0%) patients with recurrence and/or metastasis had detectable p53 mutations in their plasma DNA. CONCLUSION: p53 mutations in plasma DNA may be a useful prognostic factor and an early marker of recurrence or distant metastasis in breast cancer.

Adult↗
PubMed1990

Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a dominant mutation in a human type I collagen gene (COL1A1).

We have determined that two infants with perinatal lethal osteogenesis imperfecta in one family had the same new dominant point mutation. Although not detected in his dermal fibroblast DNA, the mutation was detected in somatic DNA from the father's hair root bulbs and lymphocytes. The mutation was also detected in the father's sperm, demonstrating that mosaicism in the father's germ line explains recurrence. The presence of both germ-line and somatic mosaicism indicates that the mutation occurred prior to segregation of the germ-line and somatic cell progenitors. About one in eight sperm carry the mutation, which implies that at least four progenitor cells populate the germ line in human males. The observation that the mosaic individual is clinically normal suggests that genetic diseases can have both qualitative and quantitative components.

Base Sequence↗
PubMed2006

Pfeiffer syndrome.

Pfeiffer syndrome is a rare autosomal dominantly inherited disorder that associates craniosynostosis, broad and deviated thumbs and big toes, and partial syndactyly on hands and feet. Hydrocephaly may be found occasionally, along with severe ocular proptosis, ankylosed elbows, abnormal viscera, and slow development. Based on the severity of the phenotype, Pfeiffer syndrome is divided into three clinical subtypes. Type 1 "classic" Pfeiffer syndrome involves individuals with mild manifestations including brachycephaly, midface hypoplasia and finger and toe abnormalities; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, developmental delay and neurological complications. Type 3 is similar to type 2 but without a cloverleaf skull. Clinical overlap between the three types may occur. Pfeiffer syndrome affects about 1 in 100,000 individuals. The disorder can be caused by mutations in the fibroblast growth factor receptor genes FGFR-1 or FGFR-2. Pfeiffer syndrome can be diagnosed prenatally by sonography showing craniosynostosis, hypertelorism with proptosis, and broad thumb, or molecularly if it concerns a recurrence and the causative mutation was found. Molecular genetic testing is important to confirm the diagnosis. Management includes multiple-staged surgery of craniosynostosis. Midfacial surgery is performed to reduce the exophthalmos and the midfacial hypoplasia.

Acrocephalosyndactylia↗
PubMed1999

The age of nonsynonymous and synonymous mutations in animal mtDNA and implications for the mildly deleterious theory.

McDonald/Kreitman tests performed on animal mtDNA consistently reveal significant deviations from strict neutrality in the direction of an excess number of polymorphic nonsynonymous sites, which is consistent with purifying selection acting on nonsynonymous sites. We show that under models of recurrent neutral and deleterious mutations, the mean age of segregating neutral mutations is greater than the mean age of segregating selected mutations, even in the absence of recombination. We develop a test of the hypothesis that the mean age of segregating synonymous mutations equals the mean age of segregating nonsynonymous mutations in a sample of DNA sequences. The power of this age-of-mutation test and the power of the McDonald/Kreitman test are explored by computer simulations. We apply the new test to 25 previously published mitochondrial data sets and find weak evidence for selection against nonsynonymous mutations.

Alleles↗
PubMedDate not supplied

BRCA2 mutations in 154 finnish male breast cancer patients.

The etiology and pathogenesis of male breast cancer (MBC) are poorly known. This is due to the fact that the disease is rare, and large-scale genetic epidemiologic studies have been difficult to carry out. Here, we studied the frequency of eight recurrent Finnish BRCA2 founder mutations in a large cohort of 154 MBC patients (65% diagnosed in Finland from 1967 to 1996). Founder mutations were detected in 10 patients (6.5%), eight of whom carried the 9346(-2) A>G mutation. Two novel mutations (4075 delGT and 5808 del5) were discovered in a screening of the entire BRCA2 coding region in 34 samples. However, these mutations were not found in the rest of the 120 patients studied. Patients with positive family history of breast and/or ovarian cancer were often BRCA2 mutation carriers (44%), whereas those with no family history showed a low frequency of involvement (3.6%; P < .0001). Finally, we found only one Finnish MBC patient with 999 del5, the most common founder mutation in Finnish female breast cancer (FBC) patients, and one that explains most of the hereditary FBC and MBC cases in Iceland. The variation in BRCA2 mutation spectrum between Finnish MBC patients and FBC patients in Finland and breast cancer patients in Iceland suggests that modifying genetic and environmental factors may significantly influence the penetrance of MBC and FBC in individuals carrying germline BRCA2 mutations in some populations.

Aged↗