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PubMed1999

Familial hypercholesterolemia. Acceptor splice site (G-->C) mutation in intron 7 of the LDL-R gene: alternate RNA editing causes exon 8 skipping or a premature stop codon in exon 8. LDL-R(Honduras-1) [LDL-R1061(-1) G-->C].

Familial hypercholesterolemia (FH) is an autosomal dominant lipoprotein disorder caused by defects in the low density lipoprotein (LDL) receptor (R) gene. We report a novel mutation of the LDL-R gene in a 38-year-old man with homozygous FH from the province of Trujilo in Northern Honduras. The patient presented with tendinous xanthomas over the extensor tendons as well as xanthelasmas at sites of surgical scars. He was diagnosed with severe coronary artery disease requiring revascularization at age 29. After an unsuccessful course of treatment with simvastatin, the patient has been treated with plasma apheresis and macromolecular plasma filtration bi-monthly. Haplotyping of the LDL-R gene revealed homozygosity for the rare 'J' allele and a loss of the EcoRV restriction cleavage site in exon 8. Single stranded conformational polymorphism of exons 3, 6, 7, 9, 10 and 8 reveals an abnormal migration pattern in exon 8. Direct sequencing of the promoter region, exons 1, 4, 8 and 13 revealed two RFLP's and a novel mutation in intron 7. This mutation consists of G-->C transposition at the acceptor splice site of exon 8 at the last nucleotide of intron 7 [LDL-R1061(-1)G-->C]. Reverse transcriptase (RT) PCR amplification of RNA from monocytes obtained from the patient reveals a decrease in LDL-R mRNA (52% of control) and skipping of exon 8 (approximately 38%, as assessed by densitometric scanning of the amplified fragments) to form a new RNA transcript that includes exons 7 and 9 without frameshift. Alternative RNA editing leads to a new cryptic acceptor splice site 17 bp downstream in exon 8 producing a frameshift mutation and a predicted premature stop codon 1138 bp from the transcriptional start site (approxiamtely 62%). Western blotting analysis using a monoclonal antibody (C7) directed at the amino terminus of the LDL-R protein reveals a marked reduction in LDL-R protein expressed in monocytes obtained from the patient. We conclude that LDL-R1061(-1)G-->C is a novel mutation of the LDL-R gene that results in marked decrease in LDL-R mRNA levels and protein expression by two alternate RNA editing mechanisms, that cause skipping of exon 8 or the use of a novel cryptic acceptor splice site in exon 8 with a frameshift and premature stop codon. The patient continues to do well on selective plasma filtration but developed bilateral severe carotid artery disease requiring surgical intervention.

Adult↗
PubMed1982

Powerful mutator activity of the polA1 mutation within the histidine region of Escherichia coli K-12.

We examined 122 spontaneous histidine auxotrophs accumulated in overnight cultures of polA1 strains of Escherichia coli K-12 at approximate frequencies of 10(-3). One hundred and thirteen appeared to be minus frameshifts, and nine appeared to be deletions. Of the frameshift mutations, 109 affected the hisC gene, and 4 affected genes hisD, hisH, hisA, and hisI. The lack of base substitutions supported the idea that polymerase-defective polA is a minus frameshift- and deletion-type mutator. Contrary to a previous report, we did not observe superior growth of PolA auxotrophs over their prototrophic progenitors (15 auxotrophs tested). We conclude that the polA1 mutation exerts a powerful mutator activity in this specific genetic context.

DNA-Directed DNA Polymerase↗
PubMed2003

Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene.

Hereditary spastic paraplegia (HSP) is a heterogeneous condition characterised in its pure form by progressive lower limb spasticity. Mutations in SPG4 (encoding spastin) may be responsible for up to 40% of autosomal dominant (AD) cases. A cohort of 41 mostly pure HSP patients from Britain and Austria, 30 of whom displayed AD inheritance, was screened for mutations in SPG4 by single strand conformation polymorphism (SSCP) analysis followed by sequencing of samples with mobility shifts. We identified eight SPG4 mutations in pure AD HSP patients, seven of which were novel: one missense mutation within the AAA cassette (1633G>T), two splice site mutations (1130-1G>T, 1853+2T>A) and four frameshift mutations (190_208dup19, 1259_1260delGT, 1702_1705delGAAG, 1845delG). A novel duplication in intron 11 (1538+42_45dupTATA) was also detected. We report the HUGO-approved nomenclature of these mutations as well. Furthermore, we detected a silent change (1004G>A; P293P), previously reported as a mutation, which was also present in controls. The frequency of SPG4 mutations detected in pure AD HSP was 33.3%, suggesting that screening of such patients for SPG4 mutations is worthwhile. Most patients will have unique mutations. Screening of SPG4 in apparently isolated cases of HSP may be of less value.

Adenosine Triphosphatases↗
PubMed2005

Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin.

We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.

Adolescent↗
PubMed1999

Germline mutations in a polycytosine repeat of the hMSH6 gene in Korean hereditary nonpolyposis colorectal cancer.

Somatic mutations within a mononucleotide repeat sequence present in the hMSH6 and hMSH3 coding regions have been frequently observed in various human cancer tissues and cell lines showing genomic instability. However, relatively few germline mutations of the repeat sequence have been identified. Two germline mutations in the hMSH6 region have been reported in hereditary nonpolyposis colorectal cancer (HNPCC); however, no germline mutations in the hMSH3 gene have been reported yet. To investigate genetic alterations within an 8 bp polycytosine repeat of the hMSH6 gene and an 8-bp polyadenine repeat of the hMSH3 gene, we amplified the mononucleotide repeat sequences of 35 HNPCC patients, 44 patients suspected of having HNPCC who did not fulfill the criteria of the International Collaborative Group on HNPCC, and 45 patients with sporadic early-onset colorectal cancer who developed colorectal cancer before the age of 40 years without any family history of colorectal cancer. Genetic alteration of the repeat sequence of the hMSH3 gene was not observed, whereas germline frame-shift mutations (one C insertion) in the hMSH6 gene were found in two of the 44 suspected HNPCC patient in whom germline mutations of hMSH2 or hMLH1 had not been detected. An identical frameshift mutation was also observed in another affected member of a suspected HNPCC family. These results suggest that the mutation of hMSH6 is responsible for tumorigenesis in minor groups of suspected HNPCC patients.

Adult↗
PubMed2001

Null mutation in the human 11-cis retinol dehydrogenase gene associated with fundus albipunctatus.

PURPOSE: Recent studies show that mutations in the gene encoding 11-cis retinol dehydrogenase are associated with fundus albipunctatus. The authors wanted to investigate whether additional, more severe, mutations in the 11-cis retinol dehydrogenase gene might be responsible for more severe forms of hereditary retinal diseases. DESIGN: Case-control molecular genetics study. PARTICIPANTS AND CONTROLS: Two index patients, 7 relatives, and 50 control individuals. METHODS: The authors screened two index patients diagnosed with fundus albipunctatus for mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene by direct sequencing. Control individuals were screened for the presence of the mutations using allele-specific oligonucleotide hybridization. MAIN OUTCOME MEASURES: Mutations in exons 2 to 5 and exon/intron boundaries of the 11-cis retinol dehydrogenase gene. RESULTS: In a compound heterozygote, two novel mutations were found: a 4 bp insertion in exon 2 and a missense mutation Cys267Trp in exon 5. In a second pedigree, a homozygous frameshift mutation in codon 43 (Arg42ct[1-bpdel]) was detected. In both families, the mutations segregate with the disease. The mutations were not found in 50 control individuals. CONCLUSIONS: On the basis of our observations, it is unlikely that mutations in the 11-cis retinol dehydrogenase gene are associated with other, possibly more severe, retinal pathologic conditions/dystrophies or syndromic diseases in which the retina is also affected.

Adult↗
PubMed1997

Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.

Oguchi disease is a recessively inherited form of stationary night blindness due to malfunction of the rod photoreceptor mechanism. Patients with this disease show a distinctive golden-brown colour of the fundus that occurs as the retina adapts to light, called the Mizuo phenomenon. Recently a defect in arrestin, a member of the rod phototransduction pathway, was found to cause this disease in some Japanese patients. As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase. This report describes an analysis of the arrestin and rhodopsin kinase genes in three unrelated cases of Oguchi disease. No defects in arrestin were detected, but all three cases had mutations in the rhodopsin kinase gene. Two cases were found to be homozygous for a deletion encompassing exon 5, predicted to lead to a nonfunctional protein. The third case was a compound heterozygote with two allelic mutations, a missense mutation (Val380Asp) affecting a residue in the catalytic domain, and a frameshift mutation (Ser536(4-bp del)) resulting in truncation of the carboxy terminus. Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness.

Alleles↗
PubMed2006

Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.

Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites.

Amino Acid Sequence↗
PubMed1999

Mutation and expression of the p51 gene in human lung cancer.

A newly identified gene, p51, is a functional and structural homologue of the p53 gene and thus a Candidate tumor suppressor gene. To elucidate the role of the p51 gene in lung carcinogenesis, we determined the sequences of exon-intron boundaries and the 5'- and 3'-flanking regions of all the 15 coding exons and performed a mutation analysis, as well as detailed analysis for gene expression. A frameshift mutation was detected in 1 of 44 lung cancer cell lines, whereas no mutation was detected in 45 primary lung cancers. Thus, p51 mutation occurs only in a small subset of lung cancer. Expression of the p51 gene was detected in 23 of 43 cell lines by Northern blot analysis and 34 of 44 by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Thus, p51 expression is low or absent in a subset of lung cancer. The deltaN isotype of p51 transcripts was dominantly expressed in several cell lines, particularly in cell lines with high levels of p51 expression. Because the deltaN isotype encodes a protein that transdominantly suppresses the transactivation function of the TA type of p51, it is possible that p51 protein is not functionally active, even in lung cancer cells with p51 mRNA expression, due to expression of dominant-negative p51 protein. These results suggested that the p51 gene is inactive in a considerable proportion of lung cancers. RT-PCR analysis also revealed the presence of a novel type of mRNA transcript, p51delta, which lacks exons 12 and 13 by alternative splicing. The delta isotype was expressed in 18 of 44 lung cancer cell lines and in diverse normal tissues. Further analysis on p51 expression in cancerous as well as noncancerous cells will provide us with valuable information for the understanding of multiple functions of the p53 family proteins in human carcinogenesis.

Base Sequence↗
PubMed1996

Five unknown mutations in the LR pyruvate kinase gene associated with severe hereditary nonspherocytic haemolytic anaemia in France.

A survey of PK-deficient patients by molecular biology techniques has been performed in France in 26 unrelated families, in which at least one mutation has been characterized. The patients, of European or North African origin, exhibited approximatively 10% of PK activity. Among the PK-R mutants described, mutation G1529-->A (Arg-509-->Gln) was the most frequent. The strategy followed for the description of PK mutants in France firstly involves determination of this mutation by PCR amplification and restriction enzyme digestion and, secondly, the sequencing of the gene for negative samples. Study of the mutation at residue 509 in 26 unrelated families indicated that 10/52 defective alleles possessed this mutation. Our study described seven different mutations; five of these have not as yet been documented. Two frameshift mutations were found: the deletion of one G base in a repetition of four Gs in position 1231-1234 (PK Mondor), del C-1527 (PK Rouen), and three missense mutations: G382-->C (Ala-114-->Pro) (PK Val-de-Marne), C398-->T (Ser-119-->Phe) (PK Beaujon), A1217-->G (Asn-392-->Ser) (PK Paris). Two mutations which were detected have been reported previously: C760-->T (Glu-240-->End) and G1529-->A (Arg-509-->Gln.

Anemia, Hemolytic↗
PubMed2004

Molecular analysis of myophosphorylase deficiency in Dutch patients with McArdle's disease.

We report on 8 Dutch patients with McArdle's disease from 6 unrelated families. Molecular analysis revealed the presence of four previously described mutations: the common R49X mutation, the IVS14+1G>A mutation and the recently reported R269X and Y84X nonsense mutations; and two new molecular defects: a missense mutation R138W in the homozygous state in two siblings, and a frameshift mutation c.1797delT. This first genetic study of patients from The Netherlands with McArdle's disease confirms that the R49X mutation is also the most common in Dutch patients, and that there is genetic heterogeneity within this population. Moreover, our data support the hypothesis that the Y84X mutation is a relatively frequent mutation in McArdle's patients with a Central European background, and expand the already crowded map of mutations within the PYGM gene responsible for McArdle's disease.

Base Sequence↗
PubMed1995

Distribution of 13 truncating mutations in the neurofibromatosis 1 gene.

Neurofibromatosis 1 (NF1) is a common genetic disorder characterized by abnormalities of tissues derived from the neural crest. To define germ-line mutations in the NF1 gene, we studied 20 patients with familial or sporadic cases of NF1 diagnosed clinically and one patient with only café-au-lait spots and no other diagnostic criteria. A protein truncation assay identified abnormal polypeptides synthesized in vitro from five RT-PCR products that represented the entire NF1 coding region. Truncated polypeptides were observed in 14 individuals. The mutations responsible for the generation of abnormal polypeptides were characterized by DNA sequencing. Thirteen previously unpublished mutations were characterized in the 14 individuals. The mutation 2027insC was observed in two unrelated individuals; the other 12 mutations were unique. The sequence changes included seven nonsense and four frameshift mutations that created premature translation termination signals, and two large in-frame deletions that led to the synthesis of truncated polypeptides. One of the mutations was found in the child with a single clinical diagnostic criterion, providing her with a presumptive diagnosis of NF1. Our results confirm that truncating mutations are frequent in both familial and sporadic NF1 cases. The identification of mutations in 14 of 21 individuals studied (67%) suggests that the use of protein truncation assays will rapidly accelerate the rate of identification of NF1 mutations. Because we scanned the entire NF1 coding region in each individual, the distribution of NF1 truncating mutations was discerned for the first time. The mutations were relatively evenly distributed throughout the coding region with no evidence for clustering.

Base Sequence↗
PubMed2004

A programmed -1 ribosomal frameshift signal can function as a cis-acting mRNA destabilizing element.

Nonsense-mediated mRNA decay (NMD) directs rapid degradation of premature termination codon (PTC)-containing mRNAs, e.g. those containing frameshift mutations. Many viral mRNAs encode polycistronic messages where programmed -1 ribosomal frameshift (-1 PRF) signals direct ribosomes to synthesize polyproteins. A previous study, which identified consensus -1 PRF signals in the yeast genome, found that, in contrast to viruses, the majority of predicted -1 PRF events would direct translating ribosomes to PTCs. Here we tested the hypothesis that a -1 PRF signal can function as a cis-acting mRNA destabilizing element by inserting an L-A viral -1 PRF signal into a PGK1 reporter construct in the 'genomic' orientation. The results show that even low levels of -1 PRF are sufficient to target the reporter mRNA for degradation via the NMD pathway, with half-lives similar to messages containing in-frame PTCs. The demonstration of an inverse correlation between frameshift efficiency and mRNA half-lives suggests that modulation of -1 PRF frequencies can be used to post-transcriptionally regulate gene expression. Analysis of the mRNA decay profiles of the frameshift-signal- containing reporter mRNAs also supports the notion that NMD remains active on mRNAs beyond the 'pioneer round' of translation in yeast.

Codon, Nonsense↗
PubMed2006

Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer.

To investigate the role of BRCA1 and BRCA2 mutations in Korean patients with sporadic breast cancer, 793 breast cancer patients were analyzed by denaturing high performance liquid chromatography and direct sequencing. The 793 breast cancer patients enrolled in this study had no family history of affected first- or second-degree relatives with breast and/or ovarian cancer. Seventy-nine different sequence variations were identified, of which 34 were novel. Fifteen deleterious mutations were detected in 20 out of 793 patients (2.5%): 11 frameshift mutations and 4 nonsense mutations (seven in BRCA1 and eight in BRCA2), and no recurrent or founder mutations were observed in BRCA mutation screening. However, three mutations (K467X, 3972delTGAG, and R2494X in BRCA2) were identified in other studies of the Korean population. Of 793 patients, the clinicopathological information was obtained in 135 patients, who included 20 deleterious mutation-positive and 115 deleterious mutation-negative groups. The median age at diagnosis, histologic type, histologic grade and T stage did not show statistically significant difference between these two groups. BRCA-mutation-associated tumors showed lower estrogen receptor, progesterone receptor, and HER-2/neu but higher p53 expression. Although poor prognostic features were noted in BRCA-associated tumors, we did not find statistically significant differences. The present study will be helpful in the evaluation of the need for the genetic screening of germline BRCA mutations and reliable genetic counseling for sporadic breast cancer patients.

Breast Neoplasms↗
PubMed2006

Two cases of severe neonatal hypertrophic cardiomyopathy caused by compound heterozygous mutations in the MYBPC3 gene.

BACKGROUND: Idiopathic (primary) hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in genes encoding sarcomeric proteins. One of the most commonly mutated HCM genes is the myosin binding protein C (MYBPC3) gene. Mutations in this gene lead mainly to truncation of the protein which gives rise to a relatively mild phenotype. Pure HCM in neonates is rare and most of the time childhood HCM occurs in association with another underlying condition. OBJECTIVE: To study the presence of mutations in the MYBPC3 gene in idiopathic childhood HCM. METHODS: MYBPC3 coding region and splice junction variation were analysed by denaturing high performance liquid chromatography (DHPLC) and sequencing in DNA isolated from two neonates with severe unexplained HCM, who died within the first weeks of life. RESULTS: Truncating mutations were found in both alleles of the MYBPC3 gene in both patients, suggesting there was no functional copy of the MYBPC3 protein. Patient 1 carried the maternally inherited c.2373_2374insG mutation and the paternally inherited splice-donor site mutation c.1624+1G-->A. Patient 2 carried the maternally inherited frameshift mutation c.3288delA (p.Glu1096fsX92) and the paternally inherited non-sense mutation c.2827C-->T (p.Arg943X). CONCLUSIONS: The findings indicate the need for mutation analysis of genes encoding sarcomeric proteins in childhood HCM and the possibility of compound heterozygosity.

Cardiomyopathy, Hypertrophic↗
PubMed2001

New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.

Hereditary hemochromatosis usually results from C282Y homozygosity in the HFE gene on chromosome 6p. Recently, a new type of hemochromatosis (HFE3) has been characterized in 2 unrelated Italian families with a disorder linked to 7q. Patients with HFE3 have transferrin receptor 2 (TFR2) inactivated by a homozygous nonsense mutation (Y250X). Here the identification of 2 new TFR2 mutations is reported. In a large inbred family from Campania, a frameshift mutation (84-88 insC) in exon 2 that causes a premature stop codon (E60X) is identified. In a single patient with nonfamilial hemochromatosis, a T-->A transversion (T515A), which causes a Methionine-->Lysine substitution at position 172 of the protein (M172K), has been characterized. TFR2 gene gives origin to 2 alternatively spliced transcripts-the alpha-transcript, which may encode a transmembrane protein, and the beta-transcript, a shorter, possibly intracellular variant. Based on their positions, the effects of the identified mutations on the 2 TFR2 forms are expected to differ. Y250X inactivates both transcripts, whereas E60X inactivates only the alpha-form. M172K has a complex effect: it causes a missense in the alpha-form, but it may also prevent the beta-form production because it affects its putative initiation codon. Analysis of the clinical phenotype of 13 HFE3 homozygotes characterized at the molecular level has shown a variable severity, from nonexpressing patients to severe clinical complications. The identification of new mutations of TFR2 confirms that this gene is associated with iron overload and offers a tool for molecular diagnosis in patients without HFE mutations.

Adolescent↗
PubMed2000

Identification and functional analysis of mutations in the hepatocyte nuclear factor-1alpha gene in anti-islet autoantibody-negative Japanese patients with type 1 diabetes.

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene are the cause of maturity-onset diabetes of the young type 3 (MODY 3), which is characterized by a severe impairment of insulin secretion and early onset of the disease. Although the majority of patients with type 1 diabetes have type 1A, immune-mediated diabetes, there is a significant percentage of the patients who have no evidence of an autoimmune disorder at the onset of disease. The aim of this study was to estimate the prevalence of MODY 3 in antiislet autoantibody negative patients with type 1 diabetes. From a large population-based sample of unrelated Japanese patients with type 1 diabetes, 28 patients who lacked autoantibodies to glutamic acid decarboxylase, islet cell antigen 512/insulinoma-associated antigen-2, phogrin (phosphate homolog of granules of insulinoma)/insulinoma-associated antigen-2beta, and insulin at the onset of type 1 diabetes were examined by PCR-based direct sequencing of the 10 exons, flanking introns, and the promoter region of the HNF-1alpha gene. Two (7.1%) of 28 autoantibody-negative patients with type 1 diabetes were identified as carrying mutations in the HNF-1alpha gene. One patient carried a frameshift mutation (Pro379fsdelCT) in exon 6, and another patient carried a novel 2-bp substitution at nucleotides +45 (G to A) and +46 (C to A) from the transcriptional site of the promoter region. These mutations were identified in heterozygous form and were not identified in 64 unrelated healthy control subjects or 54 unrelated islet autoantibody-positive patients with type 1 diabetes. Functional analysis of the mutant HNF-1alpha gene indicated that the Pro379fsdelCT mutation had no transcriptional trans-activation activity and acted in a dominant negative manner. The +45/46 GC to AA mutation in the promoter region showed reduced promoter activity by 10-20% compared to the wild-type sequence. In conclusion, about 7% of Japanese diabetic patients lacking antiislet autoantibodies initially classified as having type 1 diabetes could have diabetes caused by mutations in the HNF-1alpha gene.

Adolescent↗
PubMed2006

Mutation of RET proto-oncogene in Hirschsprung's disease and intestinal neuronal dysplasia.

AIM: To investigate the genetic relationship between Hirschsprung's disease (HD) and intestinal neuronal dysplasia (IND) in Chinese population. METHODS: Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control. Genomic DNA was extracted according to standard procedure. Exons 11,13,15,17 of RET proto-oncogene were amplified by polymerase chain reaction (PCR). The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism (SSCP) and sequencing of the positive amplified products was performed. RESULTS: Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11 at nucleotide 15165 G-->A (G667S), 2 frameshift mutations in exon 13 at nucleotide 18974 (18974insG), 1 missense mutation in exon 13 at nucleotide 18919 A-->G (K756E) and 1 silent mutation in exon 15 at nucleotide 20692 G-->A(Q916Q) were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G-->A and 1 silent mutation in exon 13 at nucleotide 18888 T-->G (L745L) were detected. No mutation was found in IND patients and controls. CONCLUSION: Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of RET proto-oncogene mutation is quite different between IND and HD in Chinese population. IND is a distinct clinical entity genetically different from HD.

Asian People↗

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