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

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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A novel missense mutation of CRYBB1 causes congenital cataract in a Chinese family

European Journal of Ophthalmology ◽

10.1177/1120672120914497 ◽

2020 ◽

pp. 112067212091449

Author(s):

Yanan Ji ◽

Xiangyu Zhao ◽

Juanmei Zhang ◽

Dan Zhang ◽

Chunliu Tian ◽

...

Keyword(s):

Missense Mutation ◽

Protein Function ◽

Congenital Cataract ◽

Family Members ◽

Causative Mutation ◽

Chinese Family ◽

Heterozygous Mutation ◽

Nuclear Cataract ◽

Mutation Site ◽

The Family

Objective of the study: To identify the pathogenic gene and mutation site of a Chinese family with congenital cataract. Methods: Eight family members and 100 controls were employed, and targeted exome sequencing was used to identify the genetically pathogenic factor of the proband. Results: Targeted next-generation sequencing identified a novel missense mutation c.209A>C (p.Q70P) of CRYBB1 gene in the family. Sanger sequencing results showed that this heterozygous mutation was a causative mutation, which was not found in unaffected family members and healthy controls. Bioinformatics predicts that the effect of this mutation on protein function is probably harmful. Conclusion: We demonstrate that c.209A>C of CRYBB1 gene is a pathogenic mutation in the family of congenital nuclear cataract in this study. This is the first report that this mutation leads to congenital nuclear cataract, which broadens the mutation spectrum of CRYBB1 gene in congenital nuclear cataract.

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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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Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy

Journal of Ophthalmology ◽

10.1155/2019/2824179 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Qin Xiang ◽

Lamei Yuan ◽

Yanna Cao ◽

Hongbo Xu ◽

Yunfeiyang Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Transforming Growth Factor ◽

Corneal Dystrophy ◽

Chinese Family ◽

Heterozygous Mutation ◽

Type I ◽

Whole Exome ◽

The Family

Background/Aims. Corneal dystrophies (CDs) belong to a group of hereditary heterogeneous corneal diseases which result in visual impairment due to the progressive accumulation of deposits in different corneal layers. So far, mutations in several genes have been responsible for various CDs. The purpose of this study is to identify gene mutations in a three-generation Hui-Chinese family associated with granular corneal dystrophy type I (GCD1). Methods. A three-generation Hui-Chinese pedigree with GCD1 was recruited for this study. Slit-lamp biomicroscopy, optical coherence tomography, and confocal microscopy were performed to determine the clinical features of available members. Whole exome sequencing was performed on two patients to screen for potential disease-causing variants in the family. Sanger sequencing was used to test the variant in the family members. Results. Clinical examinations demonstrated bilaterally abundant multiple grayish-white opacities in the basal epithelial and superficial stroma layers of corneas of the two patients. Whole exome sequencing revealed that a heterozygous missense mutation (c.1663C > T, p.Arg555Trp) in the transforming growth factor beta-induced gene (TGFBI) was shared by the two patients, and it cosegregated with this disease in the family confirmed by Sanger sequencing. Conclusions. The results suggested that the heterozygous TGFBI c.1663C > T (p.Arg555Trp) mutation was responsible for GCD1 in the Hui-Chinese family, which should be of great help in genetic counseling for this family.

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Analysis of the JAK2 Gene cDNA Full-Length In One Chinese Familial Myeloproliferative Disorders

Blood ◽

10.1182/blood.v116.21.5056.5056 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5056-5056

Author(s):

Ru Feng ◽

Lixia Hao ◽

Yongmin Zhang ◽

Yongqiang Wei ◽

Fen Huang ◽

...

Keyword(s):

Family Members ◽

Gene Mutations ◽

Myeloproliferative Disorders ◽

Full Length ◽

The Other ◽

Jak2v617f Mutation ◽

Chinese Family ◽

Heterozygous Mutation ◽

Homozygous Mutation ◽

The Family

Abstract Abstract 5056 Introduction: JAK2V617F point mutation have been confirmed to be one of the major molecular mechanism of BCR/ABL negative myeloproliferative disorders(MPD). Besides, some other gene mutations such as JAK2 exon12, MPL W515L/K, c-mpl and EPOR have extended the scope of the research in this field. Most of the MPD patients are sporadic and there are seldom reports in Chinese familial MPD. 2008 ASH metting we have reported in a Chinese family of MPD's findings, the two brothers in our hospital diagnosis for MPD (one is a PV, another is ET), then we investigated the 15 members of the family. We discovered that there were three male members carried the JAK2V617F mutation in this family, including the two MPD patients and their father, which affected in two generations. All the family members were confirmed as BCR/ABL, MPL W515L/K, c-mpl, and EPOR negative. Subsequently, in order to understand the existence of family members in addition to the gene JAK2 V617F mutation, the existence of JAK2 gene mutations in other parts of the? if other mutations in existence and the high incidence of family members of MPD? We focus on the cDNA full-length of JAK2 gene to provide some theory basis on the pathogenesis in MPD. Methods: A total of 15 family members were enrolled in our study, including 2 brothers of MPD patients (the older one was thrombocythemia (ET), and another is polycythemia vera (PV)) and the other members in the same family. The mRNA of mononuclear cells from peripheral blood sample was extracted according to the manufacturer's instruction (TAKARA). RT-PCR and DNA sequencing have been used to analyze the cDNA full-length of the JAK2 gene. Results: All of the samples can be analyzed for JAK2 cDNA full-length. 3 members carried the JAK2V617F mutation (1849G®T) in this family, including the two MPD patients and their father. And the older brother was homozygous mutation and the other two were heterozygous mutation. All of the 15 samples were JAK2 exon12 gene mutation negative. 2 persons who were the male ET patient's children had a heterozygous mutation (380G®A) in JAK2 exon 3, caused a glycine-to-asparticacid substitution at position 127. Besides, 13 persons had 489C®T mutation in exon 4 and 14 persons had 2490G→A mutation in exon 17 in this family, But they were both same-sense mutation. Conclusion: It is necessary to do routine analysis of blood and other related inspection for MPD patient's family members, so as to make diagnosis earlier. However, we are not sure that the sequencing results are unique to all the familial MPD and need to be confirmed by more cases. We still do not determine the current discovery point mutations have biological significance, still need to be further explored. Disclosures: No relevant conflicts of interest to declare.

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A COL4A5 Missense Variant in a Han-Chinese Family with X-linked Alport Syndrome

Current Molecular Medicine ◽

10.2174/1566524019666190906144214 ◽

2019 ◽

Vol 19 (10) ◽

pp. 758-765

Author(s):

Yuan Wu ◽

Yi Guo ◽

Jinzhong Yuan ◽

Hongbo Xu ◽

Yong Chen ◽

...

Keyword(s):

Hearing Loss ◽

Sanger Sequencing ◽

Alport Syndrome ◽

Genetic Defect ◽

Missense Variant ◽

Han Chinese ◽

Chinese Family ◽

Chain Gene ◽

Renal Disorder ◽

The Family

Background: Alport syndrome (AS) is an inherited familial nephropathy, characterized by progressive hematuric nephritis, bilateral sensorineural hypoacusis and ocular abnormalities. X-linked AS (XLAS) is the major AS form and is clinically heterogeneous, and it is associated with defects in the collagen type IV alpha 5 chain gene (COL4A5). Objective: The purpose of this research is to detect the genetic defect responsible for renal disorder in a 3-generation Han-Chinese pedigree. Methods: Detailed family history and clinical data of the family members were collected and recorded. Whole exome sequencing (WES) was applied in the proband to screen potential genetic variants, and then Sanger sequencing was used to verify the variant within the family. Two hundred unrelated ethnically matched normal individuals (male/female: 100/100, age 37.5 ± 5.5 years) without renal disorder were recruited as controls. Results: Three patients (I:1, II:1 and II:2) presented microscopic hematuria and proteinuria, and the patient I:1 developed uremia and end stage renal disease (ESRD) by age 55 and showed sensorineural hearing loss. Patient II:2 developed mild left ear hearing loss. Cataracts were present in patients I:1 and II:1. A COL4A5 gene missense variant, c.2156G>A (p.G719E), located in the Gly-X-Y repeats of exon 28, was identified to co-segregate with the renal disorder in this family. The variant was absent in 200 ethnically matched controls. Conclusion: By conducting WES and Sanger sequencing, a COL4A5 missense variant, c.2156G>A (p.G719E), was identified to co-segregate with the renal disorder, and it is possible that this variant is the genetic cause of the disorder in this family. Our study may extend the mutation spectrum of XLAS and may be useful for genetic counseling of this family. Further functional studies associated with genetic deficiency are warranted in the following research.

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A family study of congenital dysfibrinogenemia caused by a novel mutation in the FGA gene: A case report

Open Medicine ◽

10.1515/med-2020-0214 ◽

2020 ◽

Vol 15 (1) ◽

pp. 769-773

Author(s):

Yingli Qiao ◽

Qisi Zhang ◽

Poshi Xu ◽

Yuhui Deng

Keyword(s):

Missense Mutation ◽

Novel Mutation ◽

Screening Tests ◽

Heterozygous Mutation ◽

Thrombin Time ◽

Mutation Site ◽

Functional Activities ◽

Heterozygous Missense Mutation ◽

The Family ◽

A Chain

AbstractCongenital dysfibrinogenemia (CD) is a rare hereditary fibrinogen disorder characterized by normal fibrinogen antigen levels associated with lower functional activities. The aim of this study is to analyze the phenotype and genotype of a family of CD. Routine coagulation screening tests were performed on the proband, her parents, and her grandparents. Then, the purified genomic DNA extracted from peripheral blood was amplified by PCR, and Sanger sequencing was performed to further confirm the mutation. The prothrombin time and activated partial thromboplastin time of the proband were normal, thrombin time prolonged, and the activity of fibrinogen (Fg:Ac) decreased significantly, but fibrinogen antigen (Fg:Ag) level was normal. The coagulation function indices of the proband’s father and grandfather were similar to her, and the indices of her mother and grandmother were normal. Sequencing results showed that the proband had a heterozygous missense mutation in FGA gene c.92G > A, which caused the mutation of amino acid 31 from glycine to glutamic acid (p.Gly31Glu). Her father had the same heterozygous mutation. In conclusion, the proband suffered from CD. The change of Gly31Glu in A chain due to the c.92G > A heterozygous missense mutation in the FGA gene is the cause of CD in the family. To the best of our knowledge, the mutation site is new and first reported so far.

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A Missense Mutation in OPA1 Causes Dominant Optic Atrophy in a Chinese Family

Journal of Ophthalmology ◽

10.1155/2019/1424928 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Shaoyi Mei ◽

Xiaosheng Huang ◽

Lin Cheng ◽

Shiming Peng ◽

Tianhui Zhu ◽

...

Keyword(s):

Missense Mutation ◽

Optic Atrophy ◽

Clinical Characteristics ◽

Hand Movement ◽

Family Members ◽

Clinical Manifestations ◽

Chinese Family ◽

Variable Degree ◽

Dominant Optic Atrophy ◽

The Family

Background. To investigate the genetic causes and clinical characteristics of dominant optic atrophy (DOA) in a Chinese family. Methods. A 5-generation pedigree of 35 family members including 12 individuals affected with DOA was recruited from Shenzhen Eye Hospital, China. Four affected family members and one unaffected family member were selected for whole exome sequencing. Sanger sequencing was used to confirm and screen the identified mutation in 18 members of the family. The disease-causing mutation was identified by bioinformatics analysis and confirmed by segregation analysis. The clinical characteristics of the family members were analyzed. Results. A heterozygous missense mutation (c.1313A>G, p.D438G) in optic atrophy 1 (OPA1) was identified in 10 individuals affected with DOA in this family. None of the unaffected family members had the mutation. Patients in this family had vision loss since they were children or adolescence. The visual acuity decreased progressively to hand movement, except for one patient (IV-12) who had relatively good vision of 20/30 and 20/28. The fundus typically manifested as optic disc pallor. The visual fields, optical coherence tomography, and visual evoked potential suggested variable degree of abnormality in patients. Patients who had a history of cigarette smoking and alcohol drinking had more severe clinical manifestations. Conclusions. Our results suggest that the p.D438G mutation in OPA1 causes optic atrophy in this family. The patients who carried the mutation demonstrated heterogeneous clinical manifestations in this family. This is the first report on the c.1313A>G (p.D438G) mutation of OPA1 in a Chinese family affected with DOA.

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Clinical Diagnosis of X-Linked Spondyloepiphyseal Dysplasia Tarda and a Novel Missense Mutation in the Sedlin Gene (SEDL)

International Journal of Endocrinology ◽

10.1155/2018/8263136 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7

Author(s):

Lei Kong ◽

Dongxu Wang ◽

Shanshan Li ◽

Chengsheng Zhang ◽

Xiuyun Jiang ◽

...

Keyword(s):

Dna Sequencing ◽

Missense Mutation ◽

Genomic Dna ◽

Gene Sequencing ◽

Genetic Mutation ◽

Heterozygous Mutation ◽

Female Carrier ◽

Spondyloepiphyseal Dysplasia ◽

The Family ◽

Spondyloepiphyseal Dysplasia Tarda

Objective. Spondyloepiphyseal dysplasia tarda (SEDT) is a rare hereditary bone disease characterized by spinal and epiphyseal anomalies. We identified the disease by gene sequencing in a Chinese pedigree with SEDT. Methods. We extracted genomic DNA from five members of a four-generation Chinese SEDT kindred with three affected males and then analyzed the genetic mutation by PCR and DNA sequencing. Results. DNA sequencing showed that the genetic missense mutation occurred one bp upstream of exon 6 in the SEDL gene in two families, and a heterozygous mutation was found in a female carrier. In addition, no mutation was found in the other members of the family. Conclusion. SEDT in this family was caused by a G/C missense mutation in exon 6 of the SEDL gene, previously not shown to be associated with X-linked SEDT.

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Male Hypogonadism and Germ Cell Loss Caused by a Mutation in Polo-Like Kinase 4

Endocrinology ◽

10.1210/en.2011-1106 ◽

2011 ◽

Vol 152 (10) ◽

pp. 3975-3985 ◽

Cited By ~ 12

Author(s):

Rebecca M. Harris ◽

Jeffrey Weiss ◽

J. Larry Jameson

Keyword(s):

Male Infertility ◽

Germ Cell ◽

Missense Mutation ◽

Cell Cycle Progression ◽

Cell Loss ◽

Kinase Domain ◽

Heterozygous Mutation ◽

Male Hypogonadism ◽

Testis Size ◽

Pachytene Spermatocytes

The genetic etiologies of male infertility remain largely unknown. To identify genes potentially involved in spermatogenesis and male infertility, we performed genome-wide mutagenesis in mice with N-ethyl-N-nitrosourea and identified a line with dominant hypogonadism and patchy germ cell loss. Genomic mapping and DNA sequence analysis identified a novel heterozygous missense mutation in the kinase domain of Polo-like kinase 4 (Plk4), altering an isoleucine to asparagine at residue 242 (I242N). Genetic complementation studies using a gene trap line with disruption in the Plk4 locus confirmed that the putative Plk4 missense mutation was causative. Plk4 is known to be involved in centriole formation and cell cycle progression. However, a specific role in mammalian spermatogenesis has not been examined. PLK4 was highly expressed in the testes both pre- and postnatally. In the adult, PLK4 expression was first detected in stage VIII pachytene spermatocytes and was present through step 16 elongated spermatids. Because the homozygous Plk4I242N/I242N mutation was embryonic lethal, all analyses were performed using the heterozygous Plk4+/I242N mice. Testis size was reduced by 17%, and histology revealed discrete regions of germ cell loss, leaving only Sertoli cells in these defective tubules. Testis cord formation (embryonic day 13.5) was normal. Testis histology was also normal at postnatal day (P)1, but germ cell loss was detected at P10 and subsequent ages. We conclude that the I242N heterozygous mutation in PLK4 is causative for patchy germ cell loss beginning at P10, suggesting a role for PLK4 during the initiation of spermatogenesis.

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Case report: exome sequencing achieved a definite diagnosis in a Chinese family with muscle atrophy

BMC Neurology ◽

10.1186/s12883-021-02093-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hui Jiang ◽

Chunmiao Guo ◽

Jie Xie ◽

Jingxin Pan ◽

Ying Huang ◽

...

Keyword(s):

Exome Sequencing ◽

Muscle Atrophy ◽

Nonsense Mutation ◽

Bioinformatics Analysis ◽

Diagnostic Delay ◽

Chinese Family ◽

Skeletal Deformity ◽

Her Family ◽

Whole Exome ◽

The Family

Abstract Background Due to large genetic and phenotypic heterogeneity, the conventional workup for Charcot-Marie-Tooth (CMT) diagnosis is often underpowered, leading to diagnostic delay or even lack of diagnosis. In the present study, we explored how bioinformatics analysis on whole-exome sequencing (WES) data can be used to diagnose patients with CMT disease efficiently. Case presentation The proband is a 29-year-old female presented with a severe amyotrophy and distal skeletal deformity that plagued her family for over 20 years since she was 5-year-old. No other aberrant symptoms were detected in her speaking, hearing, vision, and intelligence. Similar symptoms manifested in her younger brother, while her parents and her older brother showed normal. To uncover the genetic causes of this disease, we performed exome sequencing for the proband and her parents. Subsequent bioinformatics analysis on the KGGSeq platform and further Sanger sequencing identified a novel homozygous GDAP1 nonsense mutation (c.218C > G, p.Ser73*) that responsible for the family. This genetic finding then led to a quick diagnosis of CMT type 4A (CMT4A), confirmed by nerve conduction velocity and electromyography examination of the patients. Conclusions The patients with severe muscle atrophy and distal skeletal deformity were caused by a novel homozygous nonsense mutation in GDAP1 (c.218C > G, p.Ser73*), and were diagnosed as CMT4A finally. This study expanded the mutation spectrum of CMT disease and demonstrated how affordable WES could be effectively employed for the clinical diagnosis of unexplained phenotypes.

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