Antithrombin niigata: a novel missense mutation (Thr194-Ile) of the antithrombin gene results in type I deficiency.
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Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical phenotype in blood cells associated with a missense mutation in the beta subunit gene (PHKB).
We have identified mutations in the phosphorylase kinase (Phk) beta subunit gene in a male patient with liver glycogenosis caused by Phk deficiency. The patient's DNA has been analyzed for mutations in the genes encoding the alpha L, beta, and gamma TL subunits of Phk, all of which can be responsible for liver glycogenosis, by a strategy primarily based on reverse transcription/polymerase chain reaction of blood RNA and complemented by analysis of genomic DNA. His alpha L and gamma TL coding sequences are normal, whereas he is compound-heterozygous for two mutations in the beta subunit gene, PHKB. The first is a splice-site mutation (IVS4 [-2A-->G]) causing the reading-frame-disrupting deletion of exon 5 in the mRNA from this allele. The second is an Ala117Pro missense mutation, also in exon 5. This is the first missense mutation identified in PHKB, as opposed to nine translation-terminating mutations described to date. It offers an explanation for the unique biochemical phenotype of this patient. In his leukocytes, low Phk activity is measured when tested with the endogenous liver isoform of phosphorylase as the protein substrate, but normal activity is observed when tested with muscle phosphorylase added in vitro. In contrast, Phk activity in his erythrocytes is low with both substrates. The missense mutation may selectively impair the interaction of Phk with one isoform of its substrate protein and may destabilize the enzyme in a cell-type-specific way. This phenotype shares some aspects with X-linked liver glycogenosis subtype 2 (XLG2), a variant of liver Phk deficiency arising from missense mutations in the alpha L subunit gene (PHKA2), but differs from XLG2 in other respects. The present case demonstrates that mutations in Phk genes other than PHKA2 can also be associated with untypically high activity in certain blood cell types. Moreover, it emphasizes that missense mutations in Phk may cause unusual patterns of tissue involvement that would not be predicted a priori from the tissue specificity of expression of the mutated gene sequences.
Blood Cells↗
Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele.
Infantile-onset glycogen storage disease type II, or Pompe disease, results from a genetic deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Sequencing of the cDNA from a cell line (GM 244) derived from a patient with Pompe disease demonstrated a T953-to-C transition that predicted a methionine-to-threonine substitution at codon 318. The basepair substitution resulted in loss of restriction-endonuclease sites for NcoI and StyI. Analysis of genomic DNA revealed both a normal and an abnormal NcoI fragment, indicating that the patient was a genetic compound. NcoI and StyI digestion of cDNA, amplified by PCR from reverse-transcribed RNA, demonstrated that greater than 95% of the GAA mRNA in GM 244 was derived from the allele carrying the missense mutation. The missense mutation was uncommon, since it was not detected in 37 additional GAA-deficient chromosomes, as determined by digestion of genomic DNA with NcoI and hybridization. The amino acid substitution predicts a new potential site for N-linked glycosylation, as well as major changes in secondary structure of the protein. We could confirm that the mutation was responsible for the enzyme deficiency by demonstrating that a hybrid minigene containing the mutation did not express GAA enzyme activity after transient gene expression. We have therefore now provided the first identification of a single-basepair missense mutation in a patient with Pompe disease and furthermore have demonstrated that the patient is a genetic compound with the second allele barely expressing mRNA.
Base Sequence↗
Missense mutations cluster within the carboxyl-terminal region of DAX-1 and impair transcriptional repression.
DAX-1 is an orphan nuclear receptor that plays a key role in the development and function of the adrenal gland and hypothalamic-pituitary gonadal axis. Mutations in the gene encoding DAX-1 result in X-linked adrenal hypoplasia congenita (AHC). Affected boys typically present with primary adrenal failure in infancy or childhood and hypogonadotropic hypogonadism at the time of puberty. The majority of DAX1 mutations described to date are nonsense or frameshift mutations that result in premature truncation of the DAX-1 protein and loss of DAX-1 repressor function. Relatively few missense mutations in DAX1 have been reported. Here, we describe missense mutations in three additional families with X-linked AHC. When combined with previous reports, the DAX1 missense mutations appear to cluster within restricted regions of the putative ligand-binding domain of DAX-1 and affect amino acids that are evolutionarily conserved, suggesting that these regions correspond to critical functional domains. Transcription assays, using a variety of artificial and native target genes, were performed to assess the effects of these mutations on the function of DAX-1. All DAX-1 missense mutant constructs showed marked loss of repressor function, with the exception of I439S, a mutation previously shown to be associated with delayed-onset adrenal failure and incomplete hypogonadotropic hypogonadism. These data indicate that most DAX1 missense mutations associated with classic AHC exhibit marked loss of function. The locations of these mutations thereby identify important functional domains in the carboxyl-terminus of the protein.
17-alpha-Hydroxyprogesterone↗
A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome.
Truncating mutations of the gene SALL4 on chromosome 20q13.13-13.2 cause Okihiro and acro-renal-ocular syndromes. Pathogenic missense mutations within the SALL4 or SALL1 genes have not yet been reported, raising the question which phenotypic features would be associated with them. Here we describe the first missense mutation within the SALL4 gene. The mutation results in an exchange of a highly conserved zinc-coordinating Histidine crucial for zinc finger (ZF) structure within a C2H2 double ZF domain to an Arginine. Molecular modeling predicts that this exchange does not result in a loss of zinc ion binding but leads to an increased DNA-binding affinity of the domain. The index patient shows mild features of Okihiro syndrome, but in addition cranial midline defects (pituitary hypoplasia and single central incisor). This finding illustrates that the phenotypic and functional effects of SALL4 missense mutations are difficult to predict, and that other SALL4 missense mutations might lead to phenotypes not overlapping with Okihiro syndrome.
Base Sequence↗
Seizure phenotypes of a family with missense mutations in SCN2A.
The seizure phenotypes of a Japanese family with missense mutations in SCN2A are described. The proband of the family had partial epilepsy after febrile seizures plus. He had three missense mutations of SCN2A (R19K, R188W, and R524Q). The R188W mutation was suggested by electrophysiologic studies to be the main disease mutation. However, it is suggested that the penetrance rate of this pedigree is extremely low, or that other genes may have modified the phenotype of the proband.
Child↗
A missense mutation in the NF2 gene results in moderate and mild clinical phenotypes of neurofibromatosis type 2.
Since the identification of the NF2 tumor suppressor gene in 1993, various mutations have been found in NF2-related tumors and in lymphocytes from NF2 patients. Most of the reported mutations result in truncated gene products. Missense mutations affecting the tumor suppressor are rare. These missense mutations would provide valuable information for the understanding of the function of the tumor suppressor, since they should affect critical parts of the protein. In this study we describe a novel point mutation in exon 15 of the NF2 gene, which is found in lymphocyte DNA of two NF2 patients from one family. This mutation is expected to result in a substitution of Pro for Gln at codon 538. Though both of the two patients developed bilateral vestibular schwannomas, the first patient showed onset of the disease at the age of 31 years and presented with various central, peripheral and abdominal tumors, while the second patient showed later onset of clinical symptoms (at age 52 years) and presented with only two additional small spinal tumors.
Adult↗
Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome.
TBX5 is a T-box transcription factor that plays a critical role in organogenesis. Seven missense mutations in TBX5 have been identified in patients with Holt-Oram syndrome characterized by congenital heart defects and upper limb abnormalities. However, the functional significance and molecular pathogenic mechanisms of these mutations are not clear. In this study we describe functional defects in DNA binding, transcriptional activity, protein-protein interaction, and cellular localization of mutant TBX5 with these missense mutations (Q49K, I54T, G80R, G169R, R237Q, R237W, and S252I). Mutations G80R, R237Q, and R237W represent a group of mutations that dramatically reduce DNA-binding activity of TBX5, leading to reduced transcription activation by TBX5 and the loss of synergy in transcriptional activation between TBX5 and NKX2.5. The second group of mutations includes Q49K, I54T, G169R, and S252I, which have no or moderate effect on DNA-binding activity and the function of transcription activation of TBX5 but cause the complete loss of synergistic transcription activity between TBX5 and NKX2.5. All seven missense mutations greatly reduced the interaction of TBX5 with NKX2.5 in vivo and in vitro. Immunofluorescent staining showed that wild type TBX5 was localized completely into the nucleus, but mutants were localized in both nucleus and cytoplasm. These results demonstrate that all seven missense mutations studied here are functional mutations with a spectrum of defects ranging from decreases in DNA-binding activity and transcriptional activation to the dramatic reduction of interaction between TBX5 and NKX2.5, and loss of synergy in transcriptional activation between these two proteins, as well as impairment in the nuclear localization of TBX5. These defects are likely central to the pathogenesis of Holt-Oram syndrome.
Abnormalities, Multiple↗
A missense mutation in the nephrin gene impairs membrane targeting.
BACKGROUND: NPHS1, which encodes nephrin, recently has been identified as the gene in which mutations cause congenital nephrotic syndrome of the Finnish type (CNF). We previously reported novel missense mutations of NPHS1 in a Japanese patient with CNF. However, the mechanism by which these missense mutations cause the disorder remains to be clarified. METHODS: Wild-type nephrin and mutated nephrin complementary DNA were each tagged by the green fluorescence protein (GFP) gene; the expressing vectors of the fusion protein were each transfected to human embryonic kidney 293 cells. We compared intracellular localization of mutated nephrin with that of wild-type nephrin by using GFP and immunostaining examination. RESULTS: In both wild-type and mutated nephrin (Glu(447)Lys), GFP and immunostaining resulted in a colocalized microgranular pattern along the cell membrane that indicated these recombinant proteins were located at the cell surface. Conversely, in mutated nephrin (Asp(819)Val), GFP aggregation was observed in the cytoplasm, and no fluorescence was observed at the cell membrane, indicating that recombinant mutated nephrin (Asp(819)Val) could not be distributed at the cell membrane and instead was retained in cytoplasm. CONCLUSION: We confirmed that the missense mutation GAC-to-GTC transversion leading to an Asp(819)Val caused the disorder. The present study analyzes in vitro distribution of nephrin with a missense point mutation. The analysis uses a new convenient method, construction of a nephrin-GFP fusion protein.
Blotting, Western↗
Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer.
The human genetic disorder ataxia-telangiectasia (A-T) is characterized by hypersensitivity to ionizing radiation and an elevated risk of malignancy. Epidemiological data support an increased risk for breast and other cancers in A-T heterozygotes. However, screening breast cancer cases for truncating mutations in the ATM (A-T mutated) gene has failed largely to reveal an increased incidence in these patients. It has been hypothesized that ATM missense mutations are implicated in breast cancer, and there is some evidence to support this. The presence of a large variety of rare missense variants in addition to common polymorphisms in ATM makes it difficult to establish such a relationship by association studies. To investigate the functional significance of these changes we have introduced missense substitutions, identified in either A-T or breast cancer patients, into ATM cDNA before establishing stable cell lines to determine their effect on ATM function. Pathogenic missense mutations and neutral missense variants were distinguished initially by their capacity to correct the radiosensitive phenotype in A-T cells. Furthermore missense mutations abolished the radiation-induced kinase activity of ATM in normal control cells, caused chromosome instability, and reduced cell viability in irradiated control cells, whereas neutral variants failed to do so. Mutant ATM was expressed at the same level as endogenous protein, and interference with normal ATM function seemed to be by multimerization. This approach represents a means of identifying genuine ATM mutations and addressing the significance of missense changes in the ATM gene in a variety of cancers including breast cancer.
Alleles↗
Identification of nine novel DHCR7 missense mutations in patients with Smith-Lemli-Opitz syndrome (SLOS).
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome caused by deficiency of 7-dehydrocholesterol reductase (DHCR7), which catalyzes the last step of endogenous cholesterol synthesis. Surveys of SLOS patients have identified more than one hundred point mutations of the DHCR7 gene, most of which are missense mutations. Here, we report the identification of nine novel missense mutations of the DHCR7 gene.
DNA Mutational Analysis↗
The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients.
We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.
Adult↗
Fibrillogenesis of tau: insights from tau missense mutations in FTDP-17.
Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) is a neurological disorder associated with tau pathology.Tau deposits in FTDP-17 brains consist of polymerized filaments of hyperphosphorylated tau, the morphology of which is determined by the nature of the tau gene mutation observed in each case. A number of mutations associated with FTDP-17 have been identified in the 5' splice site of exon 10 and in exons 9-13 of the tau gene. The exon 10 5' splice site mutations disrupt alternative splicing and thus alter the ratio of 4R and 3R Tau isoforms. The majority of Tau missense mutations decrease its ability to bind tubulin and promote microtubule assembly. The extent of reduction varies depending on the site and nature of the mutation. Some Tau missense mutations also have a direct effect on the rate and the extent of tau filament formation. In the presence of polymerization-inducing agents such as heparin or arachidonic acid, mutant tau forms polymers more efficiently than wild type tau in vitro. Tau mutations affect polymerization at both nucleation and elongation phases. One mutation (R406W) is also known to alter the susceptibility of tau to phosphorylation. Expression of mutant tau in cultured cells changes the cytoskeletal integrity of CHO and COS-7 cells, but none of the tau transfected cells display tau filament inclusions. These findings suggest involvement of at least two mechanisms in the pathogenesis of FTDP-17.
Humans↗
No missense mutation in choroideremia patients analyzed to date.
PURPOSE: To elucidate the status of a previously described missense mutation (1442A>T) reported in the Rab Escort Protein 1 gene of a patient with choroideremia. METHODS: The base substitution previously described by Donnelly et al. (Hum Mol Genet 1994;3:1017) was first confirmed by direct genomic DNA sequencing. The REP-1 cDNA region encompassing exons 10-14 was then specifically amplified from lymphocyte-derived mRNA. The effect on mRNA splicing of the mutation was analyzed by RT-PCR and cDNA sequencing. RESULTS: The 1442A>T change located at the penultimate nucleotide of exon 11 causes complete skipping of this exon during the processing of REP-1 mRNA. Loss of exon 11 leads to the translation of a premature termination codon within exon 12. CONCLUSION: RT-PCR analyses demonstrated that the 1442A>T transversion previously described as a possible causative missense mutation does act as a splice-site error and gives rise to a truncated REP-1 protein. The virtual absence of any missense mutation found to be responsible for choroideremia makes the RT-PCR-based protein truncation test the most relevant genotypic diagnostic procedure for identifying mutations in the CHM gene.
Adaptor Proteins, Signal Transducing↗
A missense mutation (Q279R) in the fumarylacetoacetate hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation.
BACKGROUND: Tyrosinemia type I, the most severe disease of the tyrosine catabolic pathway is caused by a deficiency in fumarylacetoacetate hydrolase (FAH). A patient showing few of the symptoms associated with the disease, was found to be a compound heterozygote for a splice mutation, IVS6-1g->t, and a putative missense mutation, Q279R. Analysis of FAH expression in liver sections obtained after resection for hepatocellular carcinoma revealed a mosaic pattern of expression. No FAH was found in tumor regions while a healthy region contained enzyme-expressing nodules. RESULTS: Analysis of DNA from a FAH expressing region showed that the expression of the protein was due to correction of the Q279R mutation. RT-PCR was used to assess if Q279R RNA was produced in the liver cells and in fibroblasts from the patient. Normal mRNA was found in the liver region where the mutation had reverted while splicing intermediates were found in non-expressing regions suggesting that the Q279R mutation acted as a splicing mutation in vivo. Sequence of transcripts showed skipping of exon 8 alone or together with exon 9. Using minigenes in transfection assays, the Q279R mutation was shown to induce skipping of exon 9 when placed in a constitutive splicing environment. CONCLUSION: These data suggest that the putative missense mutation Q279R in the FAH gene acts as a splicing mutation in vivo. Moreover FAH expression can be partially restored in certain liver cells as a result of a reversion of the Q279R mutation and expansion of the corrected cells.
DNA Mutational Analysis↗
Macular abnormalities and optic disk anomaly associated with a new PAX2 missense mutation.
PURPOSE: To report a family with macular abnormalities accompanied by anomalies of the optic disk and kidney associated with a new PAX2 missense mutation. DESIGN: Observational case report. METHODS: A 34-year-old female presented with horizontal nystagmus, poor visual acuity, and chronic renal failure. She had bilateral colobomatous disk anomaly and foveal hypoplasia. Her mother also had renal dysfunction and bilaterally impaired vision. Besides the optic disk dysplasia, the fovea was hypoplastic in the right eye, whereas pigmented macular atrophy was observed in the left eye. The entire coding regions of PAX2 and PAX6 were screened for mutations. RESULTS: A heterozygous mutation G755C in exon 2 of PAX2 that results in a missense mutation, R71T, was identified in the proband and her mother. No mutations were detected in PAX6. CONCLUSIONS: A new PAX2 missense mutation, R71T, may cause macular abnormalities in addition to anomalies of the optic disk and the kidney.
Abnormalities, Multiple↗
Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion.
Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen alpha-chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for 2 mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Coexpression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant beta chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation.
Adult↗
Frequent phosphorylation at serine 392 in overexpressed p53 protein due to missense mutation in carcinoma of the urinary tract.
Post-transcriptional modification of p53 by phosphorylation has been proposed to be an important mechanism of p53 stabilization and functional regulation. Phosphorylation of p53 Ser392, in particular, activates specific DNA binding functions by stabilizing p53 tetramer formation. This study evaluated the relationship between p53 Ser392 phosphorylation and various types of p53 missense mutation detected in urothelial transitional cell carcinomas (TCCs), with stratification of the mutations according to the functional domains elucidated by the crystal structure of the p53 protein. Of 41 TCCs with missense mutations, 26 (63.4%) exhibited immunopositivity with Ser392 phospho-specific p53 antibody. In comparison to structural mutations, the missense mutations at exon 7 (p=0.0307) or located in regions that affect direct DNA binding ability (p = 0.0273) were significantly associated with Ser392 immunopositivity. No statistically significant relationship was found between Ser392 immunoreactivity and other different types of p53 mutation. The prevalence of cases exhibiting Ser392-positive immunostaining was higher for high-grade (p <0.0001) and advanced-stage TCCs (p =0.0119) than for TCCs with wild-type p53. No significant relationship was found between Ser392 immunoreactivity and apoptotic index in urothelial TCCs. These in vivo findings indicate that Ser392 phosphorylation frequently occurs in mutant form p53 in TCCs. Because mutant form p53 can act dominant-negatively by heterooligomerization with wild-type p53, these findings also suggest that Ser392 phosphorylation might activate tetramer formation to promote the dominant-negative effects of mutant form p53, and thereby contribute to proliferation of aggressive TCCs.
Aged↗