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

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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Recurrent PAX 6 mutation in a Chinese family with congenital aniridia, progressive cataracts and mental retardation

European Journal of Ophthalmology ◽

10.1177/1120672118810998 ◽

2018 ◽

Vol 30 (1) ◽

pp. 181-188

Author(s):

Dou-Dou Chen ◽

Tao Yang ◽

Si-Quan Zhu

Keyword(s):

Mental Retardation ◽

Family Members ◽

Gene Mutations ◽

Chinese Family ◽

Heterozygous Mutation ◽

Pathological Feature ◽

Phosphate Backbone ◽

Symptom Complex ◽

Congenital Aniridia ◽

And Control

Background: One prominent pathological feature of congenital aniridia is hypoplasia of the iris, often accompanied by other eye abnormalities. The objective of this study is to identify gene mutations responsible for autosomal dominance in a Chinese family with congenital aniridia, progressive cataracts and mental retardation. Methods: A total of 11 family members, including 6 affected and 5 unaffected individuals were recruited. Whole exome sequencing was performed on the proband and Sanger sequencing was applied to identify the causal mutation in the other family members and control samples. Results: A heterozygous mutation, c. 112delC (p. Arg38fs) in PAX 6, was identified in the family that was associated with congenital aniridia, progressive cataracts and mental retardation. The mutation was exclusively observed in all affected individuals but not in unaffected family members or unrelated healthy controls without aniridia recruited from Beijing Tongren Hospital. Bioinformatics analysis indicated that the mutation c. 112delC (p. Arg38fs) in PAX 6 affected sugar phosphate backbone construction, leading to half reduction of the full-length protein. Other symptoms such as lens opacity, keratitis, lens dislocation, ciliary body hypoplasia, foveal hypoplasia and mental development retardation were also observed in this family. Conclusion: These results provided a new insight into the effects of PAX 6 as a mutational hotspot, with a symptom complex that includes congenital aniridia, progressive cataracts and mental retardation. These findings suggested the cognitive treatment of PAX 6-mutated individuals could be considered earlier clinically, combined with medication or surgery of congenital aniridia and progressive cataracts.

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JAK2V617F Mutation In Hematologic Malignancies In Childhood and Myeloproliferative Disorders In Adulthood

Blood ◽

10.1182/blood.v122.21.4897.4897 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4897-4897

Author(s):

Akin Yigin ◽

Bulent Ali Antmen ◽

Hatice Korkmaz Guvenmez ◽

Mustafa Yilmaz ◽

Ilgen Sasmaz ◽

...

Keyword(s):

Conflicts Of Interest ◽

Gene Mutations ◽

Primary Myelofibrosis ◽

Myeloproliferative Disorders ◽

Hematologic Malignancies ◽

The Other ◽

Jak2v617f Mutation ◽

Acute Leukemias ◽

University Departments ◽

Almost All

Abstract Introduction Mutations in JAK2 have been implicated in polycythemia vera (PV), essential thrombocythemia (ES), primary myelofibrosis (PMF) as wll as other myeloproliferative disorders. Aim In this study we aimed to investigate the frequency of JAK2V617F mutation on 216 patients with hematologic malignancies in childhood and 176 patients with myeloproliferative disorders in adulthood. Materials and method Patient group consist of 164 ALL and 52 AML patients in childhood and 79 PV, 51 ES, 22 chronic myeloid leukemia patients (CML) and 24 PMF patients in adulthood. These patients followed by Cukurova University, Departments of Pediatric and Adult Hematology, are included in this study. Blood samples were collected in these patients group and DNA was isolated using high pure template preparation kit (Roche) and stored -80oC. Gene mutations were studied using TMB (TıbMolBiol) LightMix Kit JAK2V617F genomic and analyzed by Light Cycler 2.0 Roche Diagnostic, GmBh, Germany in both groups. Findings JAK2V617F mutation was found 1 of 164 ALL patients (0,6%), 0 of 52 AML patients (0%) in childhood. Nevertheless, JAK2V617F mutation was also found 71 of 79 PV patients (89,8%), 22 of 51 ET patients (43,1%), 1 of 22 CML patients (4,5%) and 15 of 24 PMF patients (62,5%) in adulthood. Result As a result we found high frequency of JAK2V617F mutation in PV patients than the other myeloproliferative disorders. JAK2V617F mutation was significantly high in myeloproliferative disorders in adulthood comparing with childhood acute leukemias (p<0,01). Also, this mutation was significantly high in PV patients comparing with the other myeloproliferative disorders (P<0,05). We found statistically significance between genotype and allels distribution of JAK2V617F mutation (p<0.001) and determined that T-allels may be risk of disease in terms of allel distrubition (p<0.001). Thsi study is one of the widest series to investigation of JAK2V617F mutation frequency especially in childhood hematologic malignancies and we showed that this mutation is almost all 0% in this age group. On the other hand, we showed that JAK2V617F mutation with using realtime PCR test is very useful test for diagnosing PV and ET desase. Disclosures: No relevant conflicts of interest to declare.

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Novel Genetic Findings in a Chinese Family with Axenfeld-Rieger Syndrome

Journal of Ophthalmology ◽

10.1155/2017/5078079 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Kuanshu Li ◽

Liu Yang ◽

Ying Liu ◽

Ding Lin

Keyword(s):

Genetic Counseling ◽

Genetic Analysis ◽

Gene Mutation ◽

Genomic Dna ◽

Gene Mutations ◽

Chinese Family ◽

Heterozygous Mutation ◽

Homozygous Mutation ◽

Specific Therapy ◽

Rieger Syndrome

Purpose. To describe a Chinese family with Axenfeld-Rieger syndrome (ARS) and report our novel genetic findings.Methods. Nine members of the same family underwent complete ophthalmologic examinations and genetic analysis. Genomic DNA was isolated from veinal blood and amplifed using PCR; the products of PCR were sequenced and compared with FOXC1 and PITX2 genes, from which the mutations were found.Results. Through the ophthalmologic examinations, 8 subjects were diagnosed as ARS and 1 subject was normal. A homozygous mutation c.1139_1141dupGCG(p.Gly380_Ala381insGly) and a heterozygous mutation c.1359_1361dupCGG(p.Gly456_Gln457insGly) in FOXC1 were identified in all subjects. The mutation (c.-10-30T>C) was identified in PITX2 in subjects III-1 and III-3.Conclusions.We found novel gene mutations in a Chinese family with ARS, which provides us with a better understanding of the gene mutation spectrum of ARS and the assistance for the genetic counseling and gene-specific therapy in the future.

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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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Detection of the JAK2 Gene Mutation in Familial Myeloproliferative Disorders and Significance in Chinese Peoples

Blood ◽

10.1182/blood.v112.11.5263.5263 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5263-5263

Author(s):

Ru Feng ◽

Yongmin Zhang ◽

Yongqiang Wei ◽

Yu Zhan

Keyword(s):

Blood Sample ◽

Gene Mutation ◽

Peripheral Blood ◽

Family Members ◽

Myeloproliferative Disorders ◽

Jak2v617f Mutation ◽

Peripheral Blood Sample ◽

Pcr Product ◽

The Family ◽

The Way

Abstract Myeloproliferative disorders (MPDs) constitute a group of hematopoietic malignancies. Most of the MPD patient are sporadic and there are seldom reports in familial MPD. Present studies indicated that the excessus activation of signal transduction pathway of protein tyrosine kinase is an important factor in the pathogenesy of MPD. At present, except the CML, the other kinds of Ph-negative MPD are still unclear for pathogenesis. A new acquired mutation-JAK2V617F on JAK2 gene has been discovered successively in most of PV and in part of ET and IMF patient by scholars. Studies also discover that JAK2V617F mutation exists not only in the sporadic MPD but also in the familial MPD. Now only a few of studies has focus on the familial MPD abroad, and no report about JAK2V617F mutation in familial MPD chinese poeple. Methods: We mainly collected peripheral blood sample from the family members including the two MPD patients, then we took a routine blood count test and flow cytometry analysis (including CD34, CD41, CD61, CD71, CD117, GPA. Inspection of the BM smear and pathology of BM biopsy is taken when is necessary. we collected all the nucleated cells from the peripheral blood sample and then the DNA from the nucleated cells were extracted. We design a specific primer which is specific for codon V617 of the JAK2 gene according to the reference, and then amplify the target gene by PCR and confirm the PCR product by the way of electrophoresis, we use the restriction enzyme to digest the PCR product after purification. We detect another acquired functionality gene mutation (MPLW515L/K) to the ET and IMF patient who are JAK2V617F negative by the way of PCR and DNA sequencing. we also evaluated the specific markers that had been found in familial ET such as TPO and c-mpl gene mutation by the way of DNA sequence analysis for all of the member in the family, especially the ET patient and his children. An research to detect the EPOR gene mutation on the family members especially for the PV patient and his children was carried. Results: In summary, we found that many of the members are abnormal in routine blood test besides the two MPD patient, and some of them surpass the normal level. Of the member whose PLT count is much higher than normal count was also found abnormal in cell surface antigen expression, and we diagnosis it as the third MPD(ET) patient in this family combining with the result of BM cell morphologyand pathology of BM biopsy. There were total three members carried the JAK2V617F mutation in this family, including the two MPD patient and the father whose WBC count is higher than normal but without any clinical manifestation. We also found that all members who carried the JAK2V617F mutation are male, and affected in two generation of the family. Another female member whose PLT count is obviously higher than normal with JAK2V617F negative was diagnosised as JAK2V617F negative ET. Other common markers of MPD such as MPLW515L/K in JAK2V617F negative ET and TPO, c-mpl gene mutation in familial ET and EPOR gene in familial erythrocytosis could not being found in this family. Conclusion: According to the results of our study, we found that an hereditary susceptibility may exits in this family which make the members in the family easier to development into MPD, and it is necessary to take carry an regular blood routine test and other related inspection for the family member. Our study hold on an investigation and an research in a familial MPD member for reach a goal of better understanding about JAK2V617F mutation frequency and Other common markers of MPD(sporadic MPD but also familial MPD) such as MPLW515L/K, TPO, c-mp, EPOR in this family and the role of those mutation in the pathogenesy in familial MPD, we provide some theory basis to further expounding of the pathogenesis and treatment in Ph- MPD, specially in discovering, diagnosis and prevention for the disease at a early stage. No research about the JAK2V617F mutation in familial MPD at present in chinese people, Therefore, our research is in advanced in domestic study.

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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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Novel missense mutation of SASH1 in a Chinese family with dyschromatosis universalis hereditaria

BMC Medical Genomics ◽

10.1186/s12920-021-01014-w ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Lu Cao ◽

Ruixue Zhang ◽

Liang Yong ◽

Shirui Chen ◽

Hui Zhang ◽

...

Keyword(s):

Missense Mutation ◽

Sequence Alignment ◽

Multiple Sequence Alignment ◽

Molecular Genetic ◽

Family Members ◽

Clinical Manifestations ◽

Gene Mutations ◽

Mendelian Inheritance ◽

Chinese Family ◽

Multiple Sequence

Abstract Background Dyschromatosis universalis hereditaria (DUH) is a pigmentary dermatosis characterized by generalized mottled macules with hypopigmention and hyperpigmention. ABCB6 and SASH1 are recently reported pathogenic genes related to DUH, and the aim of this study was to identify the causative mutations in a Chinese family with DUH. Methods Sanger sequencing was performed to investigate the clinical manifestation and molecular genetic basis of these familial cases of DUH, bioinformatics tools and multiple sequence alignment were used to analyse the pathogenicity of mutations. Results A novel missense mutation, c.1529G>A, in the SASH1 gene was identified, and this mutation was not found in the National Center for Biotechnology Information Database of Short Genetic Variation, Online Mendelian Inheritance in Man, ClinVar, or 1000 Genomes Project databases. All in silico predictors suggested that the observed substitution mutation was deleterious. Furthermore, multiple sequence alignment of SASH1 revealed that the p.S510N mutation was highly conserved during evolution. In addition, we reviewed the previously reported DUH-related gene mutations in SASH1 and ABCB6. Conclusion Although the affected family members had identical mutations, differences in the clinical manifestations of these family members were observed, which reveals the complexity of the phenotype-influencing factors in DUH. Our findings reveal the mutation responsible for DUH in this family and broaden the mutational spectrum of the SASH1 gene.

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BETA-GLOBIN GENE MUTATIONS IN TURKISH CHILDREN WITH BETA-THALASSEMIA: RESULTS FROM A SINGLE CENTER STUDY

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2013.055 ◽

2013 ◽

Vol 5 (1) ◽

pp. e2013055 ◽

Cited By ~ 13

Author(s):

Ali Fettah ◽

Cengiz Bayram ◽

Nese Yarali ◽

Pamir Isik ◽

Abdurrahman Kara ◽

...

Keyword(s):

Globin Gene ◽

Gene Mutations ◽

Thalassemia Major ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Thalassemia Intermedia ◽

Turkish Children ◽

Tertiary Center

Introduction: The beta thalassemias are common genetic disorders in Turkey and in this retrospective study our aim was to evaluate β-globin chain mutations and the phenotypic severity of β-thalassemia patients followed-up in our hospital, a tertiary center which serves patients from all regions of Turkey. Materials and Methods: 106 pediatric patients were analysed for β-globin gene mutations by using DNA analysis. Patients were classified as having β-thalassemia major or β-thalassemia intermedia based on age at diagnosis, transfusion frequency and lowest hemoglobin concentration in between transfusions. Results: There were 106 patients (52.8% female and 47.2% male) with a mean age of 11.2±5 years (1.6 – 22.3 years). Eighty-four (79.2%) patients had β-thalassemia major, whereas the remaining 22 patients (20.8%) were identified as having β-thalassemia intermedia. Overall, 18 different mutations were detected on 212 alleles. The most frequently encountered mutation was IVS I.110 (G>A) (35.3%), followed by Codon 8 del-AA (10.4%), IVS II.1 (G>A) (8%), IVS I.1 (G>A) (7.5%), Codon 39 (C>T) (7.1%) and Codon 5 (-CT) (6.6%), which made up 79.4% of observed mutations. According to present results, IVS I.110 (G>AA) was the most frequent mutation observed in this study, as in other results from Turkey. Evaluation of β-thalassemia mutations in 106 patients with 212 alleles, revealed the presence of homozygous mutation in 85 patients (80.2%) and compound heterozygous mutation in 21 patients (19.8%). The mutations detected in patients with homozygous mutation were IVS I.110 (G>A) (38.8%), Codon 8 del –AA (11.8%), IVS II.1 (G>A) (8.2%) and IVS I.1 (G>A) (8.2%). Observed mutations in the compound heterozygotes were Codon 39 (C>T)/Codon 41-42 (-CTTT) (14.3%), IVS I.110 (G>A)/Codon 39(C>T) (14.3%), IVS I.110 (G>A)/Codon 44(-C) (14.3%), and IVS II.745 (C>G)/ 5’UTR + 22 (G>A) (9.5%). Conclusion: Our hospital is a tertiary referral center that provides care to patients from all over the country, and thus the distribution of mutations observed in the current study is significant in term of representing that of the country as a whole.

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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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Early Onset of Combined Oxidative Phosphorylation Deficiency in Two Chinese Brothers Caused by a Homozygous (Leu275Phe) Mutation in the C1QBP Gene

Frontiers in Pediatrics ◽

10.3389/fped.2020.583047 ◽

2020 ◽

Vol 8 ◽

Author(s):

Jie Wang ◽

Huan Li ◽

Min Sun ◽

Ying Yang ◽

Qianli Yang ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Early Onset ◽

Autosomal Recessive ◽

Clinical Laboratory ◽

Clinical Manifestations ◽

Hereditary Diseases ◽

Exercise Intolerance ◽

Chinese Family ◽

Heterozygous Mutation ◽

Homozygous Mutation

Mitochondrial diseases constitute a group of heterogeneous hereditary diseases caused by impairments in mitochondrial oxidative phosphorylation and abnormal cellular energy metabolism. C1QBP plays an important role in mitochondrial homeostasis. In this study, clinical, laboratory examinations, 12-lead electrocardiographic, ultrasonic cardiogram, and magnetic resonance imaging data were collected from four members of a Chinese family. Whole exome were amplified and sequenced for the proband. The structure of protein encoded by the mutation was predicted using multiple software programs. The proband was a 14-year old boy with myocardial hypertrophy, exercise intolerance, ptosis, and increased lactate. His 9-year old brother exhibited similar clinical manifestations while the phenomenon of ptosis was not as noticeable as the proband. The onset of this disease was in infancy in both cases. They were born after uneventful pregnancies of five generation blood relative Chinese parents. A homozygous mutation (Leu275Phe) in the C1QBP gene was identified in both brothers in an autosomal recessive inherited pattern. Their parents were heterozygous mutation carriers without clinical manifestations. We demonstrated that a homozygous C1QBP- P.Leu275Phe mutation in an autosomal recessive inherited mode of inheritance caused early onset combined oxidative phosphorylation deficiency 33 (COXPD 33) (OMIM:617713) in two brothers from a Chinese family.

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