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1.
Bonafé L Dermitzakis ET Unger S Greenberg CR Campos-Xavier BA Zankl A Ucla C Antonarakis SE Superti-Furga A Reymond A 《PLoS genetics》2005,1(4):e47
Cartilage-hair hypoplasia (CHH) is a pleiotropic disease caused by recessive mutations in the RMRP gene that result in a wide spectrum of manifestations including short stature, sparse hair, metaphyseal dysplasia, anemia, immune deficiency, and increased incidence of cancer. Molecular diagnosis of CHH has implications for management, prognosis, follow-up, and genetic counseling of affected patients and their families. We report 20 novel mutations in 36 patients with CHH and describe the associated phenotypic spectrum. Given the high mutational heterogeneity (62 mutations reported to date), the high frequency of variations in the region (eight single nucleotide polymorphisms in and around RMRP), and the fact that RMRP is not translated into protein, prediction of mutation pathogenicity is difficult. We addressed this issue by a comparative genomic approach and aligned the genomic sequences of RMRP gene in the entire class of mammals. We found that putative pathogenic mutations are located in highly conserved nucleotides, whereas polymorphisms are located in non-conserved positions. We conclude that the abundance of variations in this small gene is remarkable and at odds with its high conservation through species; it is unclear whether these variations are caused by a high local mutation rate, a failure of repair mechanisms, or a relaxed selective pressure. The marked diversity of mutations in RMRP and the low homozygosity rate in our patient population indicate that CHH is more common than previously estimated, but may go unrecognized because of its variable clinical presentation. Thus, RMRP molecular testing may be indicated in individuals with isolated metaphyseal dysplasia, anemia, or immune dysregulation. 相似文献
2.
Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum
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Mutations in the RMRP gene lead to a wide spectrum of autosomal recessive skeletal dysplasias, ranging from the milder phenotypes metaphyseal dysplasia without hypotrichosis and cartilage hair hypoplasia (CHH) to the severe anauxetic dysplasia (AD). This clinical spectrum includes different degrees of short stature, hair hypoplasia, defective erythrogenesis, and immunodeficiency. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA-processing ribonuclease, RNase MRP. We recently demonstrated that mutations may affect both messenger RNA (mRNA) and ribosomal RNA (rRNA) cleavage and thus cell-cycle regulation and protein synthesis. To investigate the genotype-phenotype correlation, we analyzed the position and the functional effect of 13 mutations in patients with variable features of the CHH-AD spectrum. Those at the end of the spectrum include a novel patient with anauxetic dysplasia who was compound heterozygous for the null mutation g.254_263delCTCAGCGCGG and the mutation g.195C-->T, which was previously described in patients with milder phenotypes. Mapping of nucleotide conservation to the two-dimensional structure of the RMRP gene revealed that disease-causing mutations either affect evolutionarily conserved nucleotides or are likely to alter secondary structure through mispairing in stem regions. In vitro testing of RNase MRP multiprotein-specific mRNA and rRNA cleavage of different mutations revealed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia, whereas reduced mRNA cleavage, and thus cell-cycle impairment, predicts the presence of hair hypoplasia, immunodeficiency, and hematological abnormalities and thus increased cancer risk. 相似文献
3.
Autosomal Dominant Postaxial Polydactyly, Nail Dystrophy, and Dental Abnormalities Map to Chromosome 4p16, in the Region Containing the Ellis–van Creveld Syndrome Locus 总被引:1,自引:0,他引:1
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Timothy D. Howard Alan E. Guttmacher Wendy McKinnon Mridula Sharma Victor A. McKusick Ethylin Wang Jabs 《American journal of human genetics》1997,61(6):1405-1412
We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome. 相似文献
4.
Budde SM van den Heuvel LP Janssen AJ Smeets RJ Buskens CA DeMeirleir L Van Coster R Baethmann M Voit T Trijbels JM Smeitink JA 《Biochemical and biophysical research communications》2000,275(1):63-68
Combined OXPHOS-system enzyme deficiencies are observed in approximately 25% of all OXPHOS-system disturbances. Of these, combined complex I and III deficiency is relatively scarce. So far, only mtDNA and thymidine phosphorylase (TP) mutations have been associated with combined OXPHOS-system disturbances. In this report we show, for the first time, that a nuclear gene mutation in a structural, nuclear encoded complex I gene is associated with combined complex I and III deficiency. After our initial report we describe mutations in the NDUFS4 gene of complex I in two additional patients. The first mutation is a deletion of G at position 289 or 290. Amino acid 96 changes from a tryptophan to a stop codon. The mutation was found homozygous in the patient; both parents are heterozygous for the mutation. The second mutation is a transition from C to T at cDNA position 316. Codon is changed from CGA (arginine) to TGA (stop). The patient is homozygous for the mutation; both parents are heterozygous. Both mutations in the NDUFS4 gene led to a premature stop in Leigh-like patients with an early lethal phenotype. We hypothesise that the structural integrity of the OXPHOS system, in mammal supermolecular structures, may be responsible for the observed biochemical features. 相似文献
5.
B. Thöny F. Neuheiser L. Kierat M. O. Rolland P. Guibaud T. Schlüter R. Germann R. A. Heidenreich M. Duran J. B. C. de Klerk J. E. Ayling N. Blau 《Human genetics》1998,103(2):162-167
Four patients with primapterinuria, postulated to be due to pterin-4α-carbinolamine dehydratase (PCD) deficiency, were diagnosed
by biochemical and DNA analysis. All four patients presented in the neonatal period with hyperphenylalaninemia, and elevated
neopterin and decreased biopterin levels in the urine. These symptoms are common to 6-pyruvoyltetrahydropterin synthase deficiency
and thus there is a danger of misdiagnosis. In addition, all four patients had elevated urinary excretion of primapterin (7-biopterin),
the only persistent biochemical abnormality. Analysis of fibroblast DNA from the patients identified the following mutations
in the PCBD gene: one patient homozygous for the missense mutation E96K and one homozygous for the nonsense mutation Q97X, both in exon
4; one compound heterozygote with the mutations E96K and Q97X; and one patient with two different homozygous mutations: E26X
in exon 2 and R87Q in exon 4. In two families, the parents were investigated and found to be obligate heterozygotes for particular
mutations. One sibling was found to be unaffected. These results further substantiate the idea that primapterinuria is associated
with mutations in the PCBD gene.
Received: 4 March 1998 / Accepted: 17 April 1998 相似文献
6.
Petukhova L Sousa EC Martinez-Mir A Vitebsky A Dos Santos LG Shapiro L Haynes C Gordon D Shimomura Y Christiano AM 《Genomics》2008,92(5):273-278
While there have been significant advances in understanding the genetic etiology of human hair loss over the previous decade, there remain a number of hereditary disorders for which a causative gene has yet to be identified. We studied a large, consanguineous Brazilian family that presented with woolly hair at birth that progressed to severe hypotrichosis by the age of 5, in which 6 of the 14 offspring were affected. After exclusion of known candidate genes, a genome-wide scan was performed to identify the disease locus. Autozygosity mapping revealed a highly significant region of extended homozygosity (lod score of 10.41) that contained a haplotype with a linkage lod score of 3.28. Results of these two methods defined a 9-Mb region on chromosome 13q14.11-q14.2. The interval contains the P2RY5 gene, in which we recently identified pathogenic mutations in several families of Pakistani origin affected with autosomal recessive woolly and sparse hair. After the exclusion of several other candidate genes, we sequenced the P2RY5 gene and identified a homozygous mutation (C278Y) in all affected individuals in this family. Our findings show that mutations in P2RY5 display variable expressivity, underlying both hypotrichosis and woolly hair, and underscore the essential role of P2RY5 in the tissue integrity and maintenance of the hair follicle. 相似文献
7.
Joseph B Srinivasan A Soumittra N Vidhya A Shetty NS Uthra S Kumaramanickavel G 《Journal of genetics》2002,81(1):19-23
We used multiplex PCR followed by sequencing to screen for mutations in the 14 exons of theRPE65 gene in early-hildhood-onset autosomal recessive retinitis pigmentosa (arRP) and Leber’s congenital amaurosis (LCA) patients.
The RPE65 protein is believed to play an important role in the metabolism of vitamin A in the visual cycle and mutations identified
in the gene could have implications for vitamin A-based therapeutic intervention. We were able to identify a homozygous mutation
(AAT → AAG) in exon 9 in an arRP patient and a heterozygous missense transversion (AAT → AAG) also in exon 9 of an LCA patient.
We also identified a polymorphism in exon 10 (GAG → GAA) in an arRP as well as an LCA patient. Mutation screening would be
greatly facilitated by multiplex PCR which could cut down costs, labour and time involved. The nucleotide changes observed
in this study could bede novo. Though a larger study has been undertaken, from the preliminary results it appears that in India theRPE65 gene seems to be less involved in causation of LCA. 相似文献
8.
M.-C. Romey C. Guittard J.-P. Chazalette P. Frossard K.P. Dawson M.A. Patton T. Casals T. Bazarbachi E. Girodon G. Rault D. Bozon F. Seguret J. Demaille M. Claustres 《Human genetics》1999,105(1-2):145-150
We recently reported a novel complex allele in the cystic fibrosis transmembrane regulator ( CFTR) gene, combining a sequence change in the minimal CFTR promoter (-102T>A) and a missense mutation in exon 11 [S549R(T>G)].
Here we compare the main clinical features of six patients with cystic fibrosis (CF) carrying the complex allele [-102T>A+S549R(T>G)]
with those of 16 CF patients homozygous for mutation S549R(T>G) alone. Age at diagnosis was higher, and current age was significantly
higher (P=0.0032) in the group with the complex allele, compared with the S549R/S549R group. Although the proportion of patients with
lung colonization was similar in both groups, the age at onset was significantly higher in the group with the complex allele
(P=0.0022). Patients with the complex allele also had significantly lower sweat test chloride values (P=0.0028) and better overall clinical scores (P=0.004). None of the 22 patients reported in this study had meconium ileus. All 16 patients homozygous for S549R(T>G), however,
were pancreatic insufficient, as compared with 50% of patients carrying the complex allele (P=0.013). Moreover, the unique patient homozygous for [-102T>A+S549R(T>G)] presented with a mild disease at 34 years of age.
These observations strongly suggest that the sequence change (-102T>A) in the CFTR minimal promoter could attenuate the severe clinical phenotype associated with mutation S549R(T>G).
Electronic Publication 相似文献
9.
F.M. Vaz H.R. Scholte J. Ruiter L.M. Hussaarts-Odijk R. Rodrigues Pereira S. Schweitzer J.B.C. de Klerk H.R. Waterham R.J.A. Wanders 《Human genetics》1999,105(1-2):157-161
Systemic carnitine deficiency is a potentially lethal, autosomal recessive disorder characterized by cardiomyopathy, myopathy,
recurrent episodes of hypoketotic hypoglycemia, hyperammonemia, and failure to thrive. This form of carnitine deficiency is
caused by a defect in the active cellular uptake of carnitine, and the gene encoding the high affinity carnitine transporter
OCTN2 has recently been shown to be mutated in patients suffering from this disorder. Here, we report the underlying molecular
defect in three unrelated patients. Two patients were homozygous for the same missense mutation 632A→G, which changes the
tyrosine at amino acid position 211 into a cysteine (Y211C). The third patient was homozygous for a nonsense mutation, 844C→T,
which converts the arginine at amino acid position 282 into a stop codon (R282X). Reintroduction of wild-type OCTN2 cDNA into fibroblasts of the three patients by transient transfection restored the cellular carnitine uptake, confirming
that mutations in OCTN2 are the cause of systemic carnitine deficiency.
Electronic Publication 相似文献
10.
We report a Japanese patient with Creutzfeldt-Jakob disease (CJD) with a V203I homozygous mutation of the prion protein gene (PRNP). A 73-year-old woman developed rapidly progressive gait disturbance and cognitive dysfunction. Four months after the onset, she entered a state of an akinetic mutism. Gene analysis revealed a homozygous V203I mutation in the PRNP. Familial CJD with a V203I mutation is rare, and all previously reported cases had a heterozygous mutation showing manifestations similar to those of typical sporadic CJD. Although genetic prion diseases with homozygous PRNP mutations often present with an earlier onset and more rapid clinical course than those with heterozygous mutations, no difference was found in clinical phenotype between our homozygous case and reported heterozygous cases. 相似文献
11.
Homozygosity for a newly identified missense mutation in a patient with very severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID).
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R Hirschhorn V Chakravarti J Puck S D Douglas 《American journal of human genetics》1991,49(4):878-885
We have identified a previously unrecognized missense mutation in a patient with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). The mutation is a G646-to-A transition at a CG dinucleotide and predicts a glycine-to-arginine substitution at codon 216. Computer analysis of secondary structure predicts a major alteration with loss of a beta-pleated sheet in a highly conserved region of the protein. The basepair substitution also generates a new site for the restriction enzyme BstXI in exon 7 of the genomic DNA. Digestion of genomic DNA from the patient and from his parents revealed that he was homozygous for the mutation and that his mother and father were carriers. This mutation in homozygous form appears to be associated with very severe disease, since the patient had perinatal onset of clinical manifestations of SCID, the highest concentration of the toxic metabolite deoxyATP in nine patients studied, and a relatively poor immunologic response during the initial 2 years of therapy with polyethylene glycol-adenosine deaminase. Analysis of DNA from 21 additional patients with ADA-SCID and from 19 unrelated normals revealed that, while none of the normal individuals showed the abnormal restriction fragment, two of the 21 patients studied were heterozygous for the G646-to-A mutation. 相似文献
12.
Feng Wan Lan Yu Xiaowei Qu Yanqing Xia Ke Feng Lei Zhang Na Zhang Guihua Zhao Cuilian Zhang Haibin Guo 《Journal of cellular and molecular medicine》2023,27(20):3107-3116
Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive disease manifested with recurrent infections of respiratory tract and infertility. DNAAF3 is identified as a novel gene associated with PCD and different mutations in DNAAF3 results in different clinical features of PCD patients, such as situs inversus, sinusitis and bronchiectasis. However, the sperm phenotypic characteristics of PCD males are generally poorly investigated. Our reproductive medicine centre received a case of PCD patient with infertility, who presented with sinusitis, recurrent infections of the lower airway and severe asthenozoospermia; However, no situs inversus was found in the patient. A novel homozygous mutation in DNAAF3(c.551T>A; p.V184E) was identified in the PCD patient by whole-exome sequencing. Subsequent Sanger sequencing further confirmed that the DNAAF3 had a homozygous missense variant in the fifth exon. Transmission electron microscopy and immunostaining analysis of the sperms from the patient showed a complete absence of outer dynein arms and partial absence of inner dynein arms, which resulted in the reduction in sperm motility. However, this infertility was overcome by intracytoplasmic sperm injections, as his wife achieved successful pregnancy. These findings showed that the PCD-associated pathogenic mutation within DNAAF3 also causes severe asthenozoospermia and male infertility ultimately due to sperm flagella axoneme defect in humans. Our study not only contributes to understand the sperm phenotypic characteristics of patients with DNAAF3 mutations but also expands the spectrum of DNAAF3 mutations and may contribute to the genetic diagnosis and therapy for infertile patient with PCD. 相似文献
13.
Galmiche L Serre V Beinat M Zossou R Assouline Z Lebre AS Chretien F Shenhav R Zeharia A Saada A Vedrenne V Boddaert N de Lonlay P Rio M Munnich A Rötig A 《Mitochondrion》2012,12(2):242-247
Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases. We report two novel GFM1 mutations in two unrelated patients with encephalopathy and liver failure respectively. The first patient had intrauterine growth retardation, seizures, encephalopathy and developmental delay. Brain MRI showed hypoplasia of the vermis and severe pontine atrophy of the brainstem that were similar to those reported in patients with mitochondrial translation deficiencies. The second patient had liver failure with hypoglycemia. Respiratory chain analysis showed a complex IV deficiency in muscle of both patients. A 10K SNP genotyping detected several regions of homozygosity in the two patients. In vitro translation deficiency prompted us to study genes involved in mitochondrial translation. Therefore, we sequenced the GFM1 gene, encoding the mitochondrial translation factor EFG1, included in a shared homozygous region and identified two different homozygous mutations (R671C and L398P). Modeling studies of EFG1 protein suggested that the R671C mutation disrupts an inter-subunit interface and could locally destabilize the mutant protein. The second mutation (L398P) disrupted the H-bond network in a rich-beta-sheet domain, and may have a dramatic effect on local structure. GFM1 mutations have been seldom reported and are associated with different clinical presentation. By modeling the structure of the protein and the position of the various mutations we suggest that the clinical phenotypes of the patients could be related to the localization of the mutations. 相似文献
14.
Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play
a causal role in 5–10% of newly diagnosed tumours.BRCA1 andBRCA2 gene alterations are found in the majority of these cases. The aim of this study was to analyse theBRCA1 gene in the ovarian cancer risk group to characterize the spectrum of its mutations in the Czech Republic. Five overlapping
fragments amplified on both genomic DNA and cDNA were used to screen for the whole proteincoding sequence of theBRCA1 gene. These fragments were analysed by the protein truncation test (PTT) and direct sequencing. Three inactivating mutations
were identified in the group of 30 Czech ovarian cancer patients: the 5382insC mutation in two unrelated patients and a deletion
of exons 21 and 22 in another patient. In addition, we have found an alternatively spliced product lacking exon 5 in two other
unrelated patients. The 5382insC is the most frequent alteration of theBRCA1 gene in Central and Eastern Europe. The deletion of exons 21 and 22 affects the BRCT functional domain of the BRCA1 protein.
Although large genomic rearragements are known to be relatively frequent in Western European populations, no analyses have
been performed in our region yet. 相似文献
15.
16.
M.A. Maxwell P.V. Nelson S.J. Chin B.C. Paton W.F. Carey D.I. Crane 《Human genetics》1999,105(1-2):38-44
Peroxisome biogenesis disorders are a heterogeneous group of human neurodegenerative diseases caused by peroxisomal metabolic
dysfunction. At the molecular level, these disorders arise from mutations in PEX genes that encode proteins required for the import of proteins into the peroxisomal lumen. The Zellweger syndrome spectrum
of diseases is a major sub-set of these disorders and represents a clinical continuum from Zellweger syndrome (the most severe)
through neonatal adrenoleukodystrophy to infantile Refsum disease. The PEX1 gene, which encodes a cytoplasmic AAA ATPase, is the responsible gene in more than half of the Zellweger syndrome spectrum
patients, and mutations in PEX1 can account for the full spectrum of phenotypes seen in these patients. In these studies, we have undertaken mutation analysis
of PEX1 in skin fibroblast cell lines from Australasian Zellweger syndrome spectrum patients. A previously reported common PEX1 mutation that gives rise to a G843D substitution and correlates with the less severe disease phenotypes has been found to
be present at high frequency in our patient cohort. We also report a novel PEX1 mutation that occurs at high frequency in Zellweger syndrome spectrum patients. This mutation produces a frameshift in exon 13,
a change that leads to the premature truncation of the PEX1 protein. A Zellweger syndrome patient who was homozygous for this
mutation and who survived for less than two months from birth had undetectable levels of PEX1 mRNA. This new common mutation
therefore correlates with a severe disease phenotype. We have adopted procedures for the detection of this mutation for successful
prenatal diagnosis.
Electronic Publication 相似文献
17.
Pequignot MO Desguerre I Dey R Tartari M Zeviani M Agostino A Benelli C Fouque F Prip-Buus C Marchant D Abitbol M Marsac C 《The Journal of biological chemistry》2001,276(18):15326-15329
The gene SURF1 encodes a factor involved in the biogenesis of cytochrome c oxidase, the last complex in the respiratory chain. Mutations of the SURF1 gene result in Leigh syndrome and severe cytochrome c oxidase deficiency. Analysis of seven unrelated patients with cytochrome c oxidase deficiency and typical Leigh syndrome revealed different SURF1 mutations in four of them. Only these four cases had associated demyelinating neuropathy. Three mutations were novel splicing-site mutations that lead to the excision of exon 6. Two different novel heterozygous mutations were found at the same guanine residue at the donor splice site of intron 6; one was a deletion, whereas the other was a transition [588+1G>A]. The third novel splicing-site mutation was a homozygous [516-2_516-1delAG] in intron 5. One patient only had a homozygous polymorphism in the middle of the intron 8 [835+25C>T]. Western blot analysis showed that Surf1 protein was absent in all four patients harboring mutations. Our studies confirm that the SURF1 gene is an important nuclear gene involved in the cytochrome c oxidase deficiency. We also show that Surf1 protein is not implicated in the assembly of other respiratory chain complexes or the pyruvate dehydrogenase complex. 相似文献
18.
D. Kabzińska E. Sinkiewicz-Darol I. Hausmanowa-Petrusewicz A. Kochański 《Journal of applied genetics》2010,51(2):203-209
Among 57 mutations in the peripheral myelin protein 22 gene (PMP22) identified so far in patients affected by Charcot-Marie-Tooth disease (CMT), only 8 have been shown to segregate with a
mixed phenotype of CMT and hearing impairment. In this study, we report a new Ser1 12Arg mutation in thePMP22 gene, identified in a patient with early-onset CMT and slowly progressive hearing impairment beginning in the second decade
of life. We suggest that the Ser1 12Arg mutation in thePMP22 gene might have a causative role in the early-onset CMT with hearing impairment. Thus, our study extends the spectrum of
CMT phenotypes putatively associated withPMP22 gene mutations. 相似文献
19.
Hereditary complete deficiency of complement component C1q is a rare genetic disorder that is associated with severe recurrent
infections and a high prevalence of lupus-erythematosus-like symptoms. In the past, several single nucleotide polymorphisms
have been identified in all three genes coding for the C1q A, B, and C chains. These point mutations which either lead to
termination codons, frameshift, or amino acid exchanges were thought to be responsible for these defects as no other nonsense
or missense mutations were found. As a result of the aberrations, either a nonfunctional C1q antigen is present or no C1q
protein is detectable in the patients' sera. Screening 46 individuals from seven families with different forms of C1q deficiencies
identified a homologous silent mutation at position Gly70 (GGG>GGA) of the C1q A gene of all 11 C1q-deficient patients. A high number of family members that were heterozygous for the coding mutations carried
the silent mutation in the homozygous (18%) or heterozygous (36%) state. In addition to the Gly70 mutation in the A gene,
another homozygous silent mutation (C gene at position Pro14, CCT>CCC) was detected in all C1q-deficient patients. 相似文献
20.
One adenosine deaminase allele in a patient with severe combined immunodeficiency contains a point mutation abolishing enzyme activity. 总被引:17,自引:0,他引:17
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D Valerio B M Dekker M G Duyvesteyn L van der Voorn T M Berkvens H van Ormondt A J van der Eb 《The EMBO journal》1986,5(1):113-119
We have cloned and sequenced an adenosine deaminase (ADA) gene from a patient with severe combined immunodeficiency (SCID) caused by inherited ADA deficiency. Two point mutations were found, resulting in amino acid substitutions at positions 80 (Lys to Arg) and 304 (Leu to Arg) of the protein. Hybridization experiments with synthetic oligonucleotide probes showed that the determined mutations are present in both DNA and RNA from the ADA-SCID patient. In addition, wild-type sequences could be detected at the same positions, indicating a compound heterozygosity. Studies with ADA expression clones mutagenized in vitro showed that the mutation at position 304 is responsible for ADA inactivation. 相似文献