A Novel Mutation in the Kringle IV Domain of LPA Gene Leading to Familial Cardiovascular Diseases

Abstract Background This study aims to investigate the clinical characterization and causative genetic defect of a four-generation Chinese Han family with hyperlipoproteinemia. Methods The combined use of next-generation sequencing and qPCR technique was performed to investigate genetic pathology of familial hyperlipoproteinemia. Results The clinical manifestations of the family members include hyperlipoproteinemia, early-onset hypertension, coronary heart disease, lipoma, cerebral infarction and even sudden death, and a novel heterozygous deletion of 3-16 exon of LPA gene was identified to be causative for the symptoms in the family. Conclusions A novel deletion in the LPA gene was identified in a Chinese family associated with hyperlipoproteinemia, which expands the spectrum of the LPA mutation and its associated phenotype. Keywords Copy number variation; Hyperlipoproteinemia; Kringle IV; Lipoprotein(a); LPA;

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A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

Cephalalgia ◽

10.1177/0333102419847738 ◽

2019 ◽

Vol 39 (11) ◽

pp. 1382-1395

Author(s):

Wenjing Tang ◽

Meichen Zhang ◽

Enchao Qiu ◽

Shanshan Kong ◽

Yingji Li ◽

...

Keyword(s):

Missense Mutation ◽

Novel Mutation ◽

Clinical Manifestations ◽

Pathogenic Mutation ◽

Familial Hemiplegic Migraine ◽

Chinese Family ◽

Hemiplegic Migraine ◽

Pathogenic Potential ◽

The Family

Background ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation. Methods Clinical manifestations in the family were recorded. Blood samples from patients and the unaffected members were collected for whole-exome sequencing to identify the pathogenic mutation. Seven online softwares (SIFT, PolyPhen-2, PROVEAN, PANTHER, MutationTaster2, MutationAssessor and PMut) were used for predicting the pathogenic potential of the mutation. PredictProtein, Jpred 4 and PyMOL were used to analyze structural changes of the protein. The mutation function was further tested by Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Results All patients in the family had typical hemiplegic migraine attacks. Co-segregation of the mutation with the migraine phenotype in four generations, with 10 patients, was completed. The identified novel mutation, G762S in ATP1A2, exhibited the disease-causing feature by all the predictive softwares. The mutation impaired the local structure of the protein and decreased cell viability. Conclusion G762S in ATP1A2 is a novel pathogenic mutation identified in a Chinese family with familial hemiplegic migraine, which causes loss of function by changing the protein structure of the Na+/K+-ATPase α2 subunit.

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A novel missense mutation of CRYBA1 in a northern Chinese family with inherited coronary cataract with blue punctate opacities

European Journal of Ophthalmology ◽

10.1177/11206721211008355 ◽

2021 ◽

pp. 112067212110083

Author(s):

Shu-Hua Ni ◽

Juan-Mei Zhang ◽

Jun Zhao

Keyword(s):

Missense Mutation ◽

High Throughput Sequencing ◽

Bioinformatics Analysis ◽

Genetic Defect ◽

Kinase Domain ◽

Chinese Family ◽

Heterozygous Mutation ◽

Scale Invariant ◽

The Family ◽

Northern Chinese

Purpose: To demonstrate the underlying genetic defect that contribute to inherited cataract in a northern Chinese pedigree. Methods: The study recruited a family pedigree with a diagnosis of bilateral coronary cataract with blue punctate opacities. Fourteen family members and 100 healthy volunteers were enrolled. DNA sample of the proband in this family were analyzed by high-throughput sequencing, which was then demonstrated by Sanger sequencing in the remained people in the family and 100 controls. The functional effect of mutant genes was investigated via bioinformatics analysis, including Polymorphism Phenotyping version2 (PolyPhen-2), Protein Variation Effect Analyzer (PROVEAN v1.1.3) Scale-Invariant Feature Transform (SIFT), and Mutation Taster. Results: In this three-generation family, a novel heterozygous mutation was found in the kinase domain of CRYBA1 gene (c.340C > T, p.R114C), which was only detected in patients in the family with inherited cataract and were not detected in the remained people in the family nor in normal people. The pathogenic effect of the mutation was verified via bioinformatics analysis. Conclusion: Our study presented the molecular experiments to confirm that a novel missense mutation of c.340 C > T located in exon 4 of CRYBA1 gene results in a bilateral coronary cataract with blue punctate opacities, which enriches the mutation spectrum of CRYBA1 gene in inherited cataract and deepens the understanding of the pathogenesis of inherited cataract.

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Spectrum of Ankyrin Mutations in Hereditary Spherocytosis: A Case Report and Review of the Literature

Acta Haematologica ◽

10.1159/000492024 ◽

2018 ◽

Vol 140 (2) ◽

pp. 77-86 ◽

Cited By ~ 1

Author(s):

Yeping Luo ◽

Zhuoying Li ◽

Lihua Huang ◽

Jing Tian ◽

Menglong Xiong ◽

...

Keyword(s):

Hereditary Spherocytosis ◽

Novel Mutation ◽

Laboratory Data ◽

Clinical Manifestations ◽

Mutation Spectrum ◽

Chinese Family ◽

Review Of The Literature ◽

Newborn Period ◽

Gene Splicing ◽

Generation Sequencing

Background/Aims: Hereditary spherocytosis (HS) is a common pediatric hemolytic anemia caused by congenital red blood cell defects. HS due to ankyrin 1 (ANK1) mutations is the most common type. We explored an ANK1 mutation from an HS patient and reviewed the literature. Methods: We detected the mutation in a Chinese family in which 2 members were diagnosed with HS by next-generation sequencing. The proband was diagnosed with HS in the newborn period, based on clinical manifestations, laboratory data, and family history. The mutation spectrum of the ANK1 gene was summarized based on 85 patients diagnosed with HS carrying ANK1 mutations, and the ANK1 mutation spectrum was summarized and analyzed. Results: We identified a novel mutation affecting ANK1 gene splicing (a splicing mutation) in both the patient and her mother, which is a substitution of T>G 2 nt after exon 25 in intron 26. The study expands our knowledge of the ANK1 gene mutation spectrum, providing a molecular basis for HS. Conclusion: A novel ANK1 mutation (NM_000037.3, c.2960+2T>G, intron 26) that is potentially associated with HS was identified. To date, 80 ANK1 mutations have been reported to be associated with HS in humans.

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A novel variant in PAX6 as the cause of aniridia in a Chinese family

10.21203/rs.3.rs-21412/v2 ◽

2020 ◽

Author(s):

Xin Jin ◽

Wei Liu ◽

HouBin Huang

Keyword(s):

Nonsense Mutation ◽

Novel Mutation ◽

Causative Mutation ◽

Chinese Family ◽

The Novel ◽

Targeted Next Generation Sequencing ◽

Iris Defect ◽

The Family ◽

Novel Variant ◽

Pax6 Mutation

Abstract Background: Aniridia is a kind of congenital human panocular anomaly, which is related to PAX6 commonly. Methods: A Chinese Aniridia pedigree underwent ophthalmic examinations, including visual acuity, slit lamp and fundoscopy examination. The targeted next-generation sequencing of Aniridia genes was used to identify the causative mutation. Results: A novel heterozygous PAX6 nonsense mutation c.619A>T (p.K207*) was identified in the Chinese autosomal dominant family with aniridia. Phenotypes related to the novel mutation include nystagmus, iris defect, cataract and absence of macular fovea. Conclusion: The novel nonsense mutation in PAX6 was responsible for aniridia phenotype in the family. which expands the spectrum of the PAX6 mutation and its associated phenotype.

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Cochlear Implantation in a Patient with a Novel POU3F4 Mutation and Incomplete Partition Type-III Malformation

Neural Plasticity ◽

10.1155/2020/8829587 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xiuhua Chao ◽

Yun Xiao ◽

Fengguo Zhang ◽

Jianfen Luo ◽

Ruijie Wang ◽

...

Keyword(s):

Hearing Loss ◽

Cochlear Implantation ◽

Novel Mutation ◽

Clinical Manifestations ◽

Bioinformatic Analysis ◽

Chinese Family ◽

Whole Exome ◽

Novel Variant ◽

Genetic Features ◽

The Right

Aims. This study is aimed at (1) analyzing the clinical manifestations and genetic features of a novel POU3F4 mutation in a nonsyndromic X-linked recessive hearing loss family and (2) reporting the outcomes of cochlear implantation in a patient with this mutation. Methods. A patient who was diagnosed as the IP-III malformation underwent cochlear implantation in our hospital. The genetic analysis was conducted in his family, including the whole-exome sequencing combined with Sanger sequencing and bioinformatic analysis. Clinical features, preoperative auditory and speech performances, and postoperative outcomes of cochlear implant (CI) were assessed on the proband and his family. Results. A novel variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was detected in the family, which was cosegregated with the hearing loss. This variant was absent in 200 normal-hearing persons. The phylogenetic analysis and structure modeling of Pou3f4 protein further confirmed that the novel mutation was pathogenic. The proband underwent cochlear implantation on the right ear at four years old and gained greatly auditory and speech improvement. However, the benefits of the CI declined about three and a half years postoperation. Though the right ear had been reimplanted, the outcomes were still worse than before. Conclusion. A novel frame shift variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was identified in a Chinese family with X-linked inheritance hearing loss. A patient with this mutation and IP-III malformation could get good benefits from CI. However, the outcomes of the cochlear implantation might decline as the patient grows old.

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A novel mutation in the NADH-cytochrome b5 reductase gene of a Chinese patient with recessive congenital methemoglobinemia

Blood ◽

10.1182/blood.v95.10.3250 ◽

2000 ◽

Vol 95 (10) ◽

pp. 3250-3255 ◽

Cited By ~ 21

Author(s):

Yao Wang ◽

Yu-Shui Wu ◽

Pei-Zhen Zheng ◽

Wen-Xi Yang ◽

Guo-An Fang ◽

...

Keyword(s):

Clinical Symptoms ◽

Novel Mutation ◽

Cytochrome B5 ◽

Clinical Manifestations ◽

Mutant Enzyme ◽

Chinese Family ◽

Coding Region ◽

Cytochrome B5 Reductase ◽

Nadh Cytochrome

Abstract Recessive congenital methemoglobinemia due to nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) deficiency is classified into 2 clinical types: type 1 (erythrocyte type) and type 2 (generalized type). We found a Chinese family with type 1 recessive congenital methemoglobinemia, the patients from which were diagnosed according to clinical symptoms and b5R enzyme activity in the blood cells. To learn the molecular basis of type 1 recessive congenital methemoglobinemia in this Chinese family, we isolated total RNA from the peripheral leukocytes of the propositus and b5R complementary DNA (cDNA) by reverse transcription– polymerase chain reaction (RT-PCR). The coding region of the b5R cDNA was analyzed by sequencing the cloned PCR products. The results showed that the propositus was homozygous for a G→A transition at codon 203 in exon 7, changing a cysteine to a tyrosine (Cys203Tyr). To characterize the mutant enzyme, both glutathione S-transferase (GST)-fused wild-type b5R and GST-fused mutant Cys203Tyr b5R were expressed in Escherichia coli and affinity purified. The results showed that the catalytic activity of the enzyme was not much affected by this amino acid substitution, but the mutant enzyme exhibited decreased heat stability and increased susceptibility to trypsin. These properties of the mutant enzyme would account for the restricted b5R deficiency and mild clinical manifestations of these type 1 patients. The finding of this novel mutation makes codon 203 the only position within the b5R gene at which more than 1 mutation has been found.

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Identification of a novel mutation in the CACNA1C gene in a Chinese family with autosomal dominant cerebellar ataxia

10.21203/rs.2.9243/v3 ◽

2019 ◽

Author(s):

Jiajun Chen ◽

Yajuan Sun ◽

Xiaoyang Liu ◽

Jia Li

Keyword(s):

Cerebellar Ataxia ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Novel Mutation ◽

Genetic Defect ◽

Autosomal Dominant Cerebellar Ataxia ◽

Chinese Family ◽

Autosomal Recessive Cerebellar Ataxia ◽

Progressive Cerebellar Ataxia ◽

Genetic Patterns

Abstract Background: Hereditary ataxia is a group of neurodegenerative diseases with progressive cerebellar ataxia of the gait and limbs as the main symptoms. The genetic patterns of the disease are diverse but it is mainly divided into autosomal dominant cerebellar ataxia (ADCA) and autosomal recessive cerebellar ataxia (ARCA), and about 45 pathogenic loci have been found in ADCA. The purpose of this study was to explore the genetic defect in a Chinese family with ADCA. Methods: A three-generation Chinese family with ADCA was enrolled in this study, Exome sequencing was conducted in four family members, including the proband, and verified by Sanger sequencing. Results: The rs779393130 mutation of the CACNA1C gene co-segregated with the ataxia phenotype in this family. The mutation was not detected in 50 unaffected controls. Conclusions: The rs779393130 mutation of CACNA1C may be associated with the phenotype of the disease. The CACNA1C gene encodes the Cav1.2 (alpha-1) subunit of an L-type calcium channel and this subunit may be related to the ADCA phenotype. These findings may have implications for family clinical monitoring and genetic counseling and may also help in understanding pathogenesis of this disease.

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Identification of a novel mutation in the CACNA1C gene in a Chinese family with autosomal dominant cerebellar ataxia

10.21203/rs.2.9243/v1 ◽

2019 ◽

Author(s):

Jiajun Chen ◽

Yajuan Sun ◽

Xiaoyang Liu ◽

Jia Li

Keyword(s):

Cerebellar Ataxia ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Novel Mutation ◽

Genetic Defect ◽

Autosomal Dominant Cerebellar Ataxia ◽

Chinese Family ◽

Autosomal Recessive Cerebellar Ataxia ◽

Progressive Cerebellar Ataxia ◽

Genetic Patterns

Abstract Background: Hereditary ataxia is a group of neurodegenerative diseases with progressive cerebellar ataxia of the gait and limbs as the main symptoms. The genetic patterns of the disease are diverse but it is mainly divided into autosomal dominant cerebellar ataxia (ADCA) and autosomal recessive cerebellar ataxia (ARCA), and about 45 pathogenic loci have been found in ADCA. The purpose of this study was to explore the genetic defect in a Chinese family with ADCA. Methods: A three-generation Chinese family with ADCA was enrolled in this study, Exome sequencing was conducted in four family members, including the proband, and verified by Sanger sequencing. Results: The rs779393130 mutation of the CACNA1C gene co-segregated with the ataxia phenotype in this family. The mutation was not detected in 50 unaffected controls. Conclusions: The rs779393130 mutation of CACNA1C may be associated with the phenotype of the disease. The CACNA1C gene encodes the Cav1.2 (alpha-1) subunit of an L-type calcium channel and this subunit may be related to the ADCA phenotype. These findings may have implications for family clinical monitoring and genetic counseling and may also help in understanding pathogenesis of this disease.

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Identification of a novel mutation in the CACNA1C gene in a Chinese family with autosomal dominant cerebellar ataxia

10.21203/rs.2.9243/v2 ◽

2019 ◽

Author(s):

Jiajun Chen ◽

Yajuan Sun ◽

Xiaoyang Liu ◽

Jia Li

Keyword(s):

Cerebellar Ataxia ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Novel Mutation ◽

Genetic Defect ◽

Autosomal Dominant Cerebellar Ataxia ◽

Chinese Family ◽

Autosomal Recessive Cerebellar Ataxia ◽

Progressive Cerebellar Ataxia ◽

Genetic Patterns

Abstract Background: Hereditary ataxia is a group of neurodegenerative diseases with progressive cerebellar ataxia of the gait and limbs as the main symptoms. The genetic patterns of the disease are diverse but it is mainly divided into autosomal dominant cerebellar ataxia (ADCA) and autosomal recessive cerebellar ataxia (ARCA), and about 45 pathogenic loci have been found in ADCA. The purpose of this study was to explore the genetic defect in a Chinese family with ADCA. Methods: A three-generation Chinese family with ADCA was enrolled in this study, Exome sequencing was conducted in four family members, including the proband, and verified by Sanger sequencing. Results: The rs779393130 mutation of the CACNA1C gene co-segregated with the ataxia phenotype in this family. The mutation was not detected in 50 unaffected controls. Conclusions: The rs779393130 mutation of CACNA1C may be associated with the phenotype of the disease. The CACNA1C gene encodes the Cav1.2 (alpha-1) subunit of an L-type calcium channel and this subunit may be related to the ADCA phenotype. These findings may have implications for family clinical monitoring and genetic counseling and may also help in understanding pathogenesis of this disease.

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