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PubMed2025

Novel compound heterozygous DOCK6 variants expand the mutational spectrum in prenatal diagnosis of Adams-Oliver syndrome 2.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare developmental disorder, and the DOCK6 gene is an identified AOS gene. This report highlights the prenatal diagnosis of AOS-2 by ultrasonography and genetic testing. METHODS: A growth-restricted fetus with bilateral ventriculomegaly, paraventricular calcifications, and ventricular septal defect underwent trio-whole-exome sequencing (trio-WES). Functional validation of the splice-altering variant was performed via minigene assays and protein structural modeling. RESULTS: Trio-WES revealed compound heterozygous DOCK6 variants: a paternal frameshift (c.3190_3191del; p. Leu1064Valfs60) and a maternal splice-site variant (c.3241-1G > T). Minigene assays demonstrated that c.3241-1G > T caused intron 26 retention (486 bp), introducing a premature termination codon (p. Val1081Glufs37). Structural modeling confirmed the loss of critical DHR2 domains in both truncated proteins. CONCLUSIONS: This study expands the mutational spectrum of DOCK6 and underscores the importance of combining prenatal imaging with functional genomics for early diagnosis of AOS2.

Adult↗

PubMed2006

Determination of the mutation spectrum of the EXT1/EXT2 genes in British Caucasian patients with multiple osteochondromas, and exclusion of six candidate genes in EXT negative cases.

We describe here the spectrum and distribution of mutations in the EXT1 and EXT2 genes in the largest reported British Caucasian multiple osteochondromas (MO) population. Furthermore, we report for the first time the screening of the EXT1 and EXT2 promoters, 5'UTRs, and 3'UTRs, and exclude six potential MO candidate genes in individuals without a detectable mutation within the coding region of EXT1 and EXT2. The coding exons of EXT1 and EXT2 were screened in 72 unrelated probands affected with MO. Forty-six different mutations were identified in 56 probands, of which 29 were novel. Mutation in the EXT1 and EXT2 genes each accounted for 50% of the mutations identified. Of the 72 probands, 42 were of British Caucasian descent, which when added to the 41 British Caucasian families previously reported from our total cohort, gave a total of 83 families. This cohort's proportional frequency for EXT1/EXT2 mutation was 53%/47%. We also validated the technique of high-resolution melting analysis in a blind study using 27 unique EXT1 or EXT2 mutations. This technique was found to be sensitive with a detection rate of 100% regarding heterozygote detection for EXT mutation scanning. Furthermore, this technique has a very high throughput and is very cost-effective.

Chromatography, High Pressure Liquid↗

PubMed1993

Mutational spectrum of the p53 gene in human small-cell lung cancer and relationship to clinicopathological data.

The spectrum of p53 gene mutations was determined in formalin-fixed, paraffin-embedded samples of small-cell lung cancer derived from 28 patients. By direct sequencing of exons 5, 7, and 8, including their flanking intron sequences, 18 mutations were identified in 17 tumors (61%), and in all but two of these the wild type allele was lost. In 8 cases, the mutation detected in the tumor was absent from the corresponding normal tissue, indicating that these mutations were somatically acquired. In two patients, identical mutations were found in the primary tumor and corresponding metastases. In a further case, an intrapulmonary metastasis did not show the mutation detected in the primary tumor. The local distribution of the mutations resembled that reported in non-small cell lung cancer and gave no indication of distinct bot spot regions. G-to-T transversions were the predominant type of mutation, reflecting a possible genotoxic influence of carcinogens contained in tobacco smoke. Mutations were equally distributed among tumors with intermediate and oat cell histology and did not show a significant association to age and gender of the patients. Also, no significant relationship was observed between the presence of a mutation and tumor stage (T, N, M) or survival. However, transitions at CpG dinucleotides were restricted to tumors without detectable metastases at the time of biopsy, whereas all other mutations occurred in metastasizing small cell lung cancer.

Base Sequence↗

PubMed2003

The mutation spectrum of the APC gene in FAP patients from southern Italy: detection of known and four novel mutations.

Familial adenomatous polyposis (FAP), an autosomal dominantly inherited condition accounting for about 1% of all colorectal cancers, results from mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. The clinical spectrum and severity of FAP varies greatly with the mutation site, and both between and within families. Using the protein truncation test, single strand conformation polymorphism analysis and DNA sequencing, we identified 30 (75%) mutant alleles in 40 unrelated FAP families, for a total of 22 different APC mutations. Of these, 18 are known and 4 are novel: c.1797C>A (C599X), c.893_894delAC, (c.3225T>A; c.3226C>A) and c.4526_4527insT. Of the 30 APC gene mutations, 5 (approximately 17%) are nonsense mutations, 17 (approximately 57%) are small deletions, 5 (approximately 17%) are small insertions and 3 (approximately 10%) are complete deletions. All mutations occurred in single pedigrees, except those at codons 1061 and 1062, each found in two unrelated families, and the mutation at codon 1309 in exon 15, found in five unrelated families. About 40% of mutations, mostly small deletions and insertions, are located at repeated sequences; they promote misalignment-mediated errors in DNA replication and could represent a hot spot mutation region. This study enlarges the spectrum of APC gene mutations and sheds light on the correlation between the site of APC germline mutations and clinical manifestations of FAP.

Adenomatous Polyposis Coli↗

PubMedDate not supplied

p53 gene mutation spectrum in human unknown primary tumors.

Mutations affecting the p53 gene are associated with many human malignancies, but little is known about changes in p53 in unknown primary tumors (UPTs), which are characterized as tumors with advanced stages of malignancy. We therefore investigated the frequency of p53 mutations in a series of 15 unknown primary tumor biopsies and eight cell lines established from UPTs. Mutations in the conserved regions of the p53 gene were verified by single-strand conformation polymorphism analysis of exons 5-9 and were verified by direct DNA sequencing of polymerase chain reaction products. A point mutation leading to an amino acid change in the p53 protein was found in six cases, and a mutation causing a change to termination was found in one case. A frameshift mutation was observed in one cell line. In one patient and one cell line we observed more than one mutation in the p53 coding sequence. Overall, the frequency of mutations that changed the p53 coding sequence in the UPTs we studied was 26% (6/23). Mutations were distributed in eight codons of the p53 gene. Seven of these tumors showed a reduction to homozygosity at the p53 allele, but one tumor apparently retained heterozygosity. We conclude that although UPTs represent highly metastatic advanced tumors that are expected to have a high incidence of p53 mutations, the frequency of p53 mutations is relatively low, suggesting that p53 mutations may not play a major role in the development and progression of this unique tumor type.

Amino Acid Sequence↗

PubMed2005

The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.

Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.

Child↗

PubMed1992

p53 gene mutation spectrum in hepatocellular carcinoma.

In order to clarify the significance of mutation of the p53 tumor suppressor gene in the genesis and development of human hepatocellular carcinoma (HCC) in an aflatoxin B1 low-exposure area, the spectrum, i.e., incidence, type, and site, of p53 gene mutations was examined in 169 tissue samples resected mainly from Japanese patients using single-strand conformation polymorphism analysis and direct sequencing. Forty-nine tumors (29%) showed a p53 mutation (39 point mutations and 10 frameshifts). The point mutations comprised 18 transitions, only 4 of which occurred at CpG sites, and 21 transversions. Two evolutionarily conserved domains, IV and V, contained 65% of all mutations and codon 249 was the most frequent mutation site (7/49). The spectrum of p53 mutation did not differ among HCCs in relation to the type of hepatitis virus infection, sex, age, and background liver disease of patients, tumor size, or presence of metastasis, but incidence and site were significantly associated with the degree of differentiation of cancer cells. In poorly differentiated HCC, p53 mutation was frequent (54%) and clustered on domains IV and V, whereas in well or moderately differentiated HCC, the mutation was less frequent (21%) and equally distributed on domains II to V. Restriction fragment length polymorphism analysis revealed loss of heterozygosity on chromosome 17p in 55 (69%) of 80 informative cases and in 34 (95%) of 36 cases with p53 mutation. Therefore, p53 gene mutation is suggested to occur independently of the type of viral infection or status of preexisting liver disease and to occur preferentially in moderately and poorly differentiated HCCs in association with or after loss of another p53 allele as a late event of HCC progression.

Adult↗

PubMed2001

Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations.

Neurofibromas, benign tumors that originate from the peripheral nerve sheath, are a hallmark of neurofibromatosis type 1 (NF1). Although loss of heterozygosity (LOH) is a common phenomenon in this neoplasia, it only accounts for part of the somatic NF1 mutations found. Somatic point mutations or the presence of "two hits" in the NF1 gene have only been reported for a few neurofibromas. The large size of the NF1 gene together with the multicellular composition of these tumors has greatly hampered their molecular characterization. Here, we present the somatic NF1 mutational analysis of the whole set of neurofibromas studied by our group and consisting in 126 tumors derived from 32 NF1 patients. We report the identification of 45 independent somatic NF1 mutations, 20 of which are reported for the first time. Different types of point mutations together with LOH affecting the NF1 gene and its surrounding region or extending along the 17q arm have been found. Among point mutations, those affecting the correct splicing of the NF1 gene are common, coinciding with results reported on germline NF1 mutations. In most cases, we have been able to confirm that both copies of the NF1 gene are inactivated. We have also found that both somatic and germline mutations can be expressed at the RNA level in the neoplastic cells. Furthermore, we have observed that the study of more than one tumor derived from the same patient is useful for the identification of the germline mutation. Finally, we have noticed that the culture of neurofibromas and their fibroblast clearance facilitates LOH detection in cases in which it is difficult to determine.

Alleles↗

PubMed1996

BRCA1 germline mutational spectrum in Italian families from Tuscany: a high frequency of novel mutations.

BRCA1 germline mutations confer susceptibility to familial breast and ovarian cancer. Mutational hot spots have never been detected in BRCA1 cDNA. Some mutations have been reported several times whereas some others appear to be population-related. In this study a group of 36 Italian families were analysed for BRCA1 germline mutations. All of them were screened by allele-specific oligonucleotide hybridization (ASO) for three recurrent mutations (185delAG, 5382insC, nt332-T>G). Twenty families, selected because of their high risk of carrying BRCA1 mutations, were subjected to analysis of the entire coding sequence of the gene. A total of eight mutations were found. ASO screening demonstrated only one known mutation in one patient, whereas cycle sequencing revealed five new mutations. Three of these new mutations were frameshifts: one occurred in exon 11 (1499insA), one in exon 16 (4873delCA) and one in the splice site of exon 3 (252delAAgt). Two were missense mutations (Cys64Arg; Asn158Tyr). The same frameshift mutation, 1499insA, was detected in three unrelated families. Haplotype analysis supported the hypothesis that two of these families may have had common ancestors, whereas in the third family the analysis was uninformative. BRCA1 germline mutations were found in one out of two families with ovarian cancer, in five out of eight families with breast-ovarian cancer, and in two out of 11 families with breast cancer. All three families with 1499insA mutations included at least one case of ovarian cancer. The majority of the ovarian cancers (4/5) associated with detectable BRCA1 germline mutations were of serous histotype.

Adult↗

PubMed1992

Mutation spectrum and sequence alkylation selectivity resulting from modification of bacteriophage M13mp18 DNA with S-(2-chloroethyl)glutathione. Evidence for a role of S-(2-N7-guanyl)ethyl)glutathione as a mutagenic lesion formed from ethylene dibromide.

The major DNA adduct (greater than 95% total) resulting from the bioactivation of ethylene dibromide by conjugation with GSH is S-(2-(N7-guanyl)ethyl)GSH. The mutagenic potential of this adduct has been uncertain, however, because the observed mutagenicity might be caused by other adducts present at much lower levels, e.g. S-(2-N1-adenyl)ethyl)GSH. To assess the formation of other potential adducts, S-(2-(N3-deoxycytidyl)ethyl)GSH, S-(2-(O6-deoxyguanosyl)ethyl)GSH, and S-(2-(N2-deoxyguanosyl)ethyl)GSH were prepared and used as standards in the analysis of calf thymus DNA modified by treatment with [1,2-14C]ethylene dibromide and GSH in the presence of rat liver cytosol; only minor amounts (less than 0.2%) were found. A forward mutation assay in (repair-deficient) Salmonella typhimurium TA100 and sequence analysis were utilized to determine the type, site, and frequency of mutations in a portion of the lacZ gene resulting from in vitro modification of bacteriophage M13mp18 DNA with S-(2-chloroethyl)GSH, an analog of the ethylene dibromide-GSH conjugate. An adduct level of approximately 8 nmol (mg DNA)-1 resulted in a 10-fold increase in mutation frequency relative to the spontaneous level. The spectrum of spontaneous mutations was quite varied, but the spectrum of S-(2-chloroethyl)GSH-induced mutations consisted primarily of base substitutions of which G:C to A:T transitions accounted for 75% (70% of the total mutations). All available evidence implicates S-(2-(N7-guanyl)ethyl)GSH as the cause of these mutations inasmuch as the levels of the minor adducts are not consistent with the mutation frequency observed in this system. The sequence selectivity of alkylation was determined by treatment of end-labeled lac DNA fragments with S-(2-chloroethyl)GSH, cleavage of the DNA at adduct sites, and electrophoretic analysis. Comparison of the sequence selectivity with the mutation spectrum revealed no obligate relationship between the extent of adduct formation and the number of mutations which resulted at different sites. We suggest that the mechanism of mutagenesis involves DNA sequence-dependent alterations in the interaction of the polymerase with the (modified) template and incoming nucleotide.

Alkylation↗

PubMed2004

Polymerases leave fingerprints: analysis of the mutational spectrum in Escherichia coli rpoB to assess the role of polymerase IV in spontaneous mutation.

We compared the distribution of mutations in rpoB that lead to rifampin resistance in strains with differing levels of polymerase IV (Pol IV), including strains with deletions of the Pol IV-encoding dinB gene, strains with a chromosomal copy of dinB, strains with the F'128 plasmid, and strains with plasmid amplification of either the dinB operon (dinB-yafNOP) or the dinB gene alone. This analysis identifies several hot spots specific to Pol IV which are virtually absent from the normal spontaneous spectrum, indicating that Pol IV does not contribute significantly to mutations occurring during exponential growth in liquid culture.

DNA Polymerase beta↗

PubMed2005

Evolutionary conservation and mutational spectrum of BMPR2 gene.

A variety of mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been identified in patients with pulmonary arterial hypertension. In this study, using our BMPR2 mutation database and BMPR-II protein sequences from eight distantly related species, we defined the relationship among evolutionary conservation, mutation frequency and mutation distribution. As a whole, BMPR2 is evolving slower than the average for mammalian protein-encoding genes. As expected, the kinase domain is evolving more slowly than the extracellular ligand-binding and C-terminal domains. A detailed map of evolutionary conservation shows that there are repeating peaks and valleys within the C-terminal domain, representing higher and lower evolutionary conservation. We observed a strong correlation between evolutionary conservation and the distribution of mutations along the gene. All except two, of the nineteen missense mutations occur in absolutely conserved amino acids among the vertebrate homologs. In addition, we identified six mutational hotspots (P<0.05) by comparing the observed distribution of mutations to the pattern expected from a random multinomial distribution. Furthermore, analysis of the sequence environment surrounding the mutations revealed a specific pattern of mutagenesis. Over 22% of all single base-paired substitutions and 30% of all deletions and insertions are situated within tandem or non-tandem direct repeats of at least 5-bp and may be explained by slipped-mispairing model of mutagenesis. Also, over 59% of single base-paired substitutions versus 20% of deletions and insertions are located in perfect palindromic sequences that could produce "hairpin-loop" secondary structures with relatively high thermodynamic stability under physiological conditions. In addition, 3.7% of single base-paired substitutions versus 30% of deletions and insertions are located either within or in close proximity to the Krawczak and Cooper consensus sequence (TG A/G A/G G/T A/C). Further study of the mechanism of mutagenesis in BMPR2 may help identify other potentially mutable sites and differentiate between deleterious mutations and harmless polymorphic variants.

Amino Acid Sequence↗

PubMed2003

Clinical and molecular characterization of 6 patients affected by severe deficiency of coagulation factor V: Broadening of the mutational spectrum of factor V gene and in vitro analysis of the newly identified missense mutations.

Severe factor V (FV) deficiency is a rare bleeding disorder, whose genetic bases have been characterized only in a limited number of cases. We investigated 6 unrelated patients with extremely reduced plasma FV levels, associated with a bleeding tendency ranging from moderately severe to severe. Clinical manifestations were substantially concordant with the previously established spectrum of hemorrhagic symptoms of the disease. Molecular analysis of FV gene identified 9 different mutations, 7 hitherto unknown, and 2 previously reported (Arg712ter and Tyr1702Cys). Four of 6 analyzed patients were compound heterozygotes, indicating the high allelic heterogeneity of this disease. Among novel mutations, 5 led to premature termination codons, because of nonsense (Arg1002ter, Arg1606ter, and Trp1854ter), or frameshift mutations (5127-5128insA and 6122-6123insAACAG). The remaining 2 were missense mutations (Cys472Gly and Val1813Met), located in FV A2 and A3 domains. Their effect on FV expression was studied by transient transfection experiments, demonstrating that the presence of each mutation impaired FV secretion. These data increase the number of severe FV deficiency-causing mutations by about 50%. The high number of "private" mutations identified in FV-deficient families indicates that full mutational screening of FV gene is still required for molecular diagnosis.

Adolescent↗

PubMed2000

X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function.

PURPOSE: To assess the frequency of RPGR and RP2 mutations in a set of 85 patients with X-linked retinitis pigmentosa (XLRP) and to compare the visual function of patients with mutations in RPGR versus RP2. METHODS: Eighty-five unrelated patients with XLRP were ascertained, mainly from North America. The single-strand conformation polymorphism (SSCP) and a direct sequencing technique were used to screen their DNA for mutations in the coding region and splice sites of RPGR and RP2. The Snellen visual acuities, visual field areas, and 0.5-Hz and 30-Hz electroretinograms (ERGs) were measured in male patients. The visual function parameters were compared using multiple regression analysis. RESULTS: A wide spectrum of mutations was found in both genes, including missense, nonsense, splice-site, and frameshift mutations. Twenty putative pathogenic mutations in RPGR, 15 of which were novel, were found in 22 patients (26%), whereas 6 mutations in RP2, 4 of which were novel, were found in 6 patients (7%). A high fraction of the mutations in both genes affected amino acid residues within or adjacent to presumed functional domains. Comparison of visual function between comparably aged patients with mutations in RPGR versus RP2 showed that, on average, patients with RPGR mutations have lower ERG amplitudes and smaller visual field areas. CONCLUSIONS: Mutations in RPGR and RP2 genes together account for approximately 33% of cases of XLRP in North America. Patients with RPGR mutations have less overall retinal function on average than those with RP2 mutations, on the basis of measurements of visual field areas and full-field ERG amplitudes.

Adolescent↗

PubMed2000

Mutation spectrum of MSH3-deficient HHUA/chr.2 cells reflects in vivo activity of the MSH3 gene product in mismatch repair.

The endometrial tumor cell line HHUA carries mutations in two mismatch repair (MMR) genes MSH3 and MSH6. We have established an MSH3-deficient HHUA/chr.2 cell line by introducing human chromosome 2, which carries wild-type MSH6 and MSH2 genes, to HHUA cells. Introduction of chromosome 2 to HHUA cells partially restored G:G MMR activity to the cell extract and reduced the frequency of mutation at the hypoxanthine-guanine phosphoribosyltransferase (hprt*) locus to about 3% that of the parental HHUA cells, which is five-fold the frequency in MMR-proficient cells, indicating that the residual mutator activity in HHUA/chr.2 is due to an MSH3-deficiency in these cells. The spectrum of mutations occurring at the HPRT locus of HHUA/chr.2 was determined with 71 spontaneous 6TG(r) clones. Base substitutions and +/-1 bp frameshifts were the major mutational events constituting, respectively, 54% and 42% of the total mutations, and more than 70% of them occurred at A:T sites. A possible explanation for the apparent bias of mutations to A:T sites in HHUA/chr.2 is haploinsufficiency of the MSH6 gene on the transferred chromosome 2. Comparison of the mutation spectra of HHUA/chr.2 with that of the MSH6-deficient HCT-15 cell line [S. Ohzeki, A. Tachibana, K. Tatsumi, T. Kato, Carcinogenesis 18 (1997) 1127-1133.] suggests that in vivo the MutSalpha (MSH2:MSH6) efficiently repairs both mismatch and unpaired extrahelical bases, whereas MutSbeta (MSH2:MSH3) efficiently repairs extrahelical bases and repairs mismatch bases to a limited extent.

Amino Acid Substitution↗

PubMed2002

Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A-->G mutation of the untranslated RMRP.

Pleiotropic, recessively inherited cartilage-hair hypoplasia (CHH) is due to mutations in the untranslated RMRP gene on chromosome 9p13-p12 encoding the RNA component of RNase MRP endoribonuclease. We describe 36 different mutations in this gene in 91 Finnish and 44 non-Finnish CHH families. Based on their nature and localisation, these mutations can be classified into three categories: mutations affecting the promoter region, small changes of conserved nucleotides in the transcript, and insertions and duplications in the 5' end of the transcript. The only known functional region that seemed to avoid mutations was a nucleolar localisation signal region between nucleotides 23-62. The most common mutation in CHH patients was a base substitution G for A at nucleotide 70. This mutation contributed 92% of the mutations in the Finnish CHH patients. Our results using linkage disequilibrium based maximum likelihood estimates with close markers, genealogical studies, and haplotype data suggested that the mutation was introduced to Finland some 3900-4800 years ago, and before the expansion of the population. The same major mutation accounted for 48% of the mutations among CHH patients from other parts of Europe, North and South America, the Near East, and Australia. In the non-Finnish CHH families, the A70G mutation segregated with the same major haplotype, although shorter, as in most of the Finnish families. In 23 out of these 27 chromosomes, the common region extended over 60 kb, and, therefore, all the chromosomes most likely arose from a solitary event many thousands of years ago.

Cartilage Diseases↗

PubMed2003

Mutation spectrum of FOXC1 and clinical genetic heterogeneity of Axenfeld-Rieger anomaly in India.

PURPOSE: Axenfeld-Rieger anomaly (ARA) is a form of anterior segment dysgenesis of the eye, mainly caused by mutations in the FOXC1 gene. We had earlier reported a novel mutation in the wing region of FOXC1 in an autosomal dominant family. The present study was aimed to identify the spectrum of mutations in the FOXC1 gene in a cohort of Indian ARA patients from different ethnic backgrounds, and to understand its role in the disease pathogenesis. METHODS: Two new autosomal dominant families and seven sporadic cases of ARA from different ethnic backgrounds were screened for mutations by direct sequencing of the coding region of the FOXC1 gene. Another autosomal dominant ARA family that was previously reported by us was also included for comparative analysis of clinical genetic parameters. The segregation of the mutations in the autosomal dominant families was analyzed by haplotype and restriction analysis. Genotype-phenotype correlation were also undertaken to study the role of FOXC1 in phenotypic manifestation in the patient cohort. RESULTS: Three of the nine ARA cases harbored mutations in FOXC1, of which two novel nonsense mutations Q2X and Q123X, resulted in haploinsufficiency of the gene product. The missense mutation (M161K) that we previously reported in an autosomal dominant family was also found in another family. Haplotype analysis of these two families suggested multiple founders in the same ethnic group. The mutations resulted in variable expressions of phenotype among the patients as assessed from their prognosis based on visual outcomes. CONCLUSIONS: Significant genetic heterogeneity of FOXC1 was observed in a multi-ethnic population studied in this region of India resulting in variable ARA phenotypes. The different visual outcome seen in the patients suggest a variable expression of FOXC1 and also provide some insight for understanding the gene functions in this population.

Adolescent↗

PubMed1994

p53 gene mutation spectrum in hepatocellular carcinomas in Hong Kong Chinese.

To examine the significance of mutation of the p53 tumour suppressor gene in the development of human hepatocellular carcinoma in a high-prevalence area for hepatitis B viral infection but a low-exposure area for aflatoxin B1, the spectrum of p53 gene mutations was examined in 21 tumour samples from Hong Kong Chinese patients, all of whom were HBsAg positive. DNA sequencing covering exons 5 to 9 of the p53 gene and Hae III restriction enzyme digestion for preliminary assessment of mutation at codon 249 were performed. Immunohistochemical staining with anti-p53 monoclonal antibodies was done on both tumour and nontumour liver tissues. Six tumours (28.6%) showed a p53 mutation and all were point mutations. Of the six point mutations, two (9.5%) were at codon 249 and both were G to T transversions (AGG-->ATG and AGG-->AGT transversions). The remaining point mutations were transversions scattered at codon 172 (exon 5), 214 (exon 6), 273 (exon 8) and 330 (exon 9). Mutated p53 protein was detected in five of these six cases with demonstrable point mutations by DNA sequencing, in contrast to none detected in all of the 15 cases without demonstrable point mutations. The presence of p53 mutations, including those at codon 249, did not show a significant association with tumour size, sex, age, tumour invasiveness in terms of liver invasion, microsatellites and venous permeation, cirrhosis and encapsulation, but tumours with low cellular differentiation tended to have a higher incidence (71%) of point mutations than those with high cellular differentiation (8%). In conclusion, both the overall p53 mutation rate and that a codon 249 in HCC in Hong Kong Chinese are lower than those reported in tumours from China and sub-Saharan Africa. The low mutation rate at codon 249 is compatible with a low aflatoxin exposure. A special type of p53 mutation has not been found to be associated with hepatitis B viral infection. Mutations of p53 gene tends to occur in tumours with low cellular differentiation, suggesting a late occurrence in the event of tumour progression.

Carcinoma, Hepatocellular↗