Molecular defects in hemophilia A: identification and characterization of mutations in the factor VIII gene and family analysis
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Nonsense mutation
Factor IX
Compound heterozygosity
Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis caused by mutations of the ECM1 gene. The common variations of the ECM1 gene are nonsense and missense mutations, and in rare instance, compound heterozygotes may occur. We describe two siblings of LP from a nonconsanguineous family of China who were detected novel compound heterozygous mutations of c. 157C >T(p. R53X) in exon 3 and c. 857G >A (p. C286Y) in exon 7 of the ECM1 gene. Their mother was a carrier of missense mutation of c. 857G >A in exon 7 of ECM1, their father and one of the old sisters were the carriers of nonsense mutation of c. 157C >T in exon 3, respectively. All the carriers presented normally. The results support the opinion that the mutations of the ECM1 gene for LP are of varieties.
Compound heterozygosity
Nonsense mutation
Genodermatosis
Nonsense
Chinese family
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Friedreich's ataxia is a neurodegenerative disorder associated with a GAA trinucleotide repeat expansion in intron 1 of the frataxin (FXN) gene. It is the most common autosomal recessive cerebellar ataxia, with a mean age of onset at 16 years. Nearly 95-98% of patients are homozygous for a 90-1300 GAA repeat expansion with only 2-5% demonstrating compound heterozygosity. Compound heterozygous individuals have a repeat expansion in one allele and a point mutation/deletion/insertion in the other. Compound heterozygosity and point mutations are very rare causes of Friedreich's ataxia and nonsense mutations are a further rarity among point mutations. We report a rare compound heterozygous Friedrich's ataxia patient who was found to have one expanded GAA FXN allele and a nonsense point mutation in the other. We summarize the four previously published cases of nonsense mutations and compare the phenotype to that of our patient. We compared clinical information from our patient with other nonsense FXN mutations reported in the literature. This nonsense mutation, to our knowledge, has only been described once previously; interestingly the individual was also of Cuban ancestry. A comparison with previously published cases of nonsense mutations demonstrates some common clinical characteristics.
Nonsense mutation
Compound heterozygosity
Nonsense
Frataxin
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Nonsense mutation
Compound heterozygosity
Nonsense
Stop codon
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Nonsense mutation
Compound heterozygosity
Heterozygote advantage
Nonsense
Congenital muscular dystrophy
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The second most common cause of congenital adrenal hyperplasia is 11β-hydroxylase deficiency, an autosomal recessive disorder. We performed genetic analysis of CYP11B1, the gene encoding steroid 11β-hydroxylase, in three patients with classic 11β-hydroxylase deficiency. Herein we describe the first splice donor site mutation, a new nonsense mutation, and a new missense mutation in this disorder. An African-American patient was found to be a compound heterozygote for a codon 318+1G→A substitution at the 5′-splice donor site of intron 5, in combination with Q356X, a nonsense mutation previously reported in an African-American patient. A Caucasian patient was found to be a compound heterozygote with a novel missense mutation, T318R, in combination with a previously reported 28-bp deletion in exon 2. A different mutation at codon 318 (T318M) has been described previously. A Caucasian patient was heterozygous for a novel nonsense mutation (Q19X) in exon 2. The second mutation was not identified in this patient. Multiple apparent polymorphisms were also observed. Two of these polymorphisms in CYP11B1 represent sequences from CYP11B2, suggesting that gene conversion may have occurred. In summary, we have identified three novel mutations and two previously reported mutations in CYP11B1 patients with 11β-hydroxylase deficiency. Our data suggest the presence of a mutational hot spot at codon 318 of CYP11B1, and the possibility of a founder effect in frequently identified mutations.
Nonsense mutation
Compound heterozygosity
Steroid 11-beta-hydroxylase
Splice site mutation
Nonsense
Stop codon
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Glanzmann's thrombasthenia
Compound heterozygosity
Nonsense mutation
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In this study, a new alpha globin gene mutation on the α2-globin gene is reported. This mutation resulted in a Lys > stop codon substitution at position 127 which was detected in four individuals (three males and one female). DNA sequencing revealed this mutation in unrelated persons in Khuzestan province, Southwestern Iran of Lor ethnicity. This mutation caused no severe hematological abnormalities in the carriers. From the nature of substituted residues in α2-globin, it is widely expected that this mutation leads to unstable and truncated protein and should be detected in couples at risk for α-thalassemia.
Nonsense mutation
Hemoglobinopathy
Alpha globulin
Alpha (finance)
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Nonsense mutation
Nonsense
Stop codon
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Acrodermatitis enteropathica is rare autosomal recessive disorder characterized by a severe nutritional zinc deficiency. We and others have recently identified the human gene encoding an intestinal zinc transporter of the ZIP family, SLC39A4, as the mutated gene in acrodermatitis enteropathica (AE). A first mutation screening in 8 AE families (15 patients out of 36 individuals) revealed the presence of six different mutations described elsewhere. Based on these results, we have evaluated the involvement of SLC39A4 in 14 patients of 12 additional AE pedigees coming either from France, Tunisia, Austria or Lithuania. A total of 7 SLC39A4 mutations were identified (1 deletion, 2 nonsense, 2 missense, and 2 modifications of splice site), of which 4 are novel: a homozygous nonsense mutation in 3 consanguineous Tunisian families [c.143T>G (p.Leu48X)], a heterozygous nonsense mutation (c.1203G>A (p.Trp401X)) in a compound heterozygote from Austria also exhibiting an already known missense mutation, and distinct homozygous mutations in families from France or Tunisia [c.475-2A>G and c.184T>C (p.Cys62Arg)]. Furthermore, two other potential mutations [c.850G>A (p.Glu284Lys) and c.193-113T>C] were also observed at homozygous state in a French family formerly described. This study brings to 21 the number of reported SLC39A4 mutations in AE families.
Acrodermatitis enteropathica
Nonsense mutation
Compound heterozygosity
Nonsense
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A 26-year-old man who had a history of recurrent spontaneous nasal bleeding was admitted to our hospital with uncontrolled traumatic subdural hemorrhage. His plasma factor VII activity was less than 10% of normal. DNA sequence analysis revealed that the proband had a compound heterozygote for a novel nonsense mutation (F7 NM_000131.2 c.345C > A; p.Cys115X) in exon 4 encoding the EGF1 domain and a known missense mutation (F7 NM_000131.2 c.1027G > A; p.Gly343Ser) in exon 8 encoding the serine protease domain of F7. The same F7 Gly343Ser mutation was present in the asymptomatic father, who exhibited a modest reduction in the plasma level of factor VII activity (48%).
Compound heterozygosity
Nonsense mutation
Proband
Heterozygote advantage
Nonsense
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