scholarly journals Mutational Analysis of Compound Heterozygous Mutation P.q6x/p.h232r in Srd5a2 Causing 46,xy Disorder of Sex Development

2022 ◽  
Author(s):  
Hui Yang ◽  
Liwei Li ◽  
Junhong Zhang ◽  
Qing Li ◽  
Li Qiao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mutational Analysis ◽  
Catalytic Efficiency ◽  
Hek293 Cells ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Disorder Of Sex Development ◽  
Sex Development ◽  
The Family

Abstract Background: Over 100 mutations in the SRD5A2 gene have been identified in subjects with 46,XY disorder of sex development (DSD). Exploration of SRD5A2 mutations and elucidation of the molecular mechanisms behind their effects should reveal the functions of the domains of the 5α-reductase 2 enzyme and identify the cause of 46,XY DSD. Previously, we reported a novel compound heterozygous p.Q6X/p.H232R mutation of the SRD5A2 gene in a case with 46,XY DSD. Whether the compound heterozygous p.Q6X/p.H232R mutation in this gene causes 46,XY DSD requires further exploration. Results: To clarify the cause of 46,XY DSD in the affected family focused on here, SRD5A2 sequencing was performed. Heterozygous p.H232R mutation was identified in the proband’s father, so we concluded that this mutation originated from the paternal side of the family and did not cause 46,XY DSD. Meanwhile, heterozygous p.Q6X mutation was identified in the proband’s mother, maternal uncle, and maternal grandfather, indicating that this mutation originated from maternal side of the family and did not cause 46,XY DSD. To clarify the effect of the p.H232R mutation in SRD5A2 on dihydrotestosterone (DHT) production, p.H232R mutant SRD5A2 plasmids were transfected into HEK293 cells. LC-MS indicated that DHT production decreased compared with that in cells transfected with wild-type SRD5A2.Conclusions: Our findings confirmed that the compound heterozygous p.Q6X/p.H232R mutation in the SRD5A2 gene is the cause of 46,XY DSD. p.H232R mutation reduced DHT production while attenuating the catalytic efficiency of the 5α-reductase 2 enzyme.

scholarly journals Mutational Analysis of a Novel Mutation (p.H232R) in the SRD5A2 Causing 46,XY Disorder of Sex Development

2021 ◽  
Author(s):  
Liwei Li ◽  
Junhong Zhang ◽  
Qing Li ◽  
Li Qiao ◽  
Pengcheng Li ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Mutational Analysis ◽  
Novel Mutation ◽  
Catalytic Efficiency ◽  
Hek293 Cells ◽  
Compound Heterozygous ◽  
Wild Type ◽  
Disorder Of Sex Development ◽  
Maternal Grandfather ◽  
Sex Development

Abstract Background: Over 100 mutations in SRD5A2 gene have been identified in subjects with 46,XY DSD. Exploring SRD5A2 mutation and elucidating its molecular mechanism will find the domains function of 5α-reductase 2 enzyme and identify the cause of 46,XY DSD. Previously, we reported a novel compound heterozygous p.H232R/p.Q6X mutation of SRD5A2 gene in a case with 46,XY DSD. Whether the compound heterozygous p.Q6X/p.H232R mutation in SRD5A2 gene causes 46,XY DSD occurrence is needed to be further explored. Results: In order to clarify the cause of 46,XY DSD in the case’s family, SRD5A2 sequencing were performed. The heterozygous p.H232R mutation were identified in the case’s father, so we concluded that the heterozygous p.H232R mutation originated from paternal family and didn’t cause 46,XY DSD occurrence. The heterozygous p.Q6X mutation were identified in the case’s mother, maternal uncle and maternal grandfather, indicating that the heterozygous p.Q6X mutation descended from maternal family and didn’t cause 46,XY DSD occurrence. In order to clarify p.H232R mutation in SRD5A2 on DHT production, p.H232R mutant SRD5A2 plasmids were transfected with HEK293 cells and LC-MS detected that DHT production decreased compared with wild-type SRD5A2 infected ones.Conclusions: Our findings confirmed that the compound heterozygous p.Q6X/p.H232R mutation in SRD5A2 gene is the cause of 46,XY DSD. p.H232R mutation reduced DHT production while attenuated 5α-reductase 2 enzymatic catalytic efficiency.

scholarly journals A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings

2021 ◽  
Vol 12 ◽  
Author(s):  
Yeran Yang ◽  
Jiwei Chen ◽  
Hong Qin ◽  
Yaqiong Jin ◽  
Li Zhang ◽  
...  
Keyword(s):  
Cell Line ◽  
Brca2 Gene ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Rna Seq ◽  
The Family ◽  
Neuroblastic Tumors ◽  
Family Case ◽  
The Impact

ObjectivesTo investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.Materials and MethodsOne family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.ResultsA novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings’ mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.ConclusionIn summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.

scholarly journals Case Report: Novel Compound Heterozygous RNASEH2B Mutations Cause Aicardi–Goutières Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Jessica Garau ◽  
Silvia Masnada ◽  
Francesca Dragoni ◽  
Daisy Sproviero ◽  
Federico Fogolari ◽  
...  
Keyword(s):  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Clinical Genetic ◽  
Protein Levels ◽  
The Family ◽  
Lower Protein ◽  
The Stability ◽  
Rnase H2 ◽  
Generation Sequencing

Aicardi–Goutières Syndrome (AGS) is a rare disorder characterized by neurological and immunological signs. In this study we have described a child with a phenotype consistent with AGS carrying a novel compound heterozygous mutation in RNASEH2B gene. Next Generation Sequencing revealed two heterozygous variants in RNASEH2B gene. We also highlighted a reduction of RNase H2B transcript and protein levels in all the family members. Lower protein levels of RNase H2A have been observed in all the members of the family as well, whereas a deep depletion of RNase H2C has only been identified in the affected child. The structural analysis showed that both mutations remove many intramolecular contacts, possibly introducing conformational rearrangements with a decrease of the stability of RNase H2B and strongly destabilizing the RNase H2 complex. Taken together, these results highlight the importance of an integrated diagnostic approach which takes into consideration clinical, genetic, and molecular analyses.

scholarly journals A Novel Compound Heterozygous Mutation in ABCB4 Gene Leading to Cholelithiasis, Progressive Familial Intrahepatic Cholestasis (Type 3), and Cirrhosis in a Child

2020 ◽  
Vol 10 (01) ◽  
pp. e134-e136
Author(s):  
Nida Mirza ◽  
Smita Malhotra ◽  
Anupam Sibal
Keyword(s):  
Intrahepatic Cholestasis ◽  
Gall Stone ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Initial Symptom ◽  
Progressive Familial Intrahepatic Cholestasis ◽  
Presenting Symptoms ◽  
Abcb4 Gene ◽  
Type 3

AbstractProgressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive disorders of childhood which presents with intermittent or progressive episodes of cholestasis, with jaundice and pruritus as most common presenting symptoms. PFIC type 3 occurs due to mutations in the ABCB4 gene, mutation in this gene has wide spectrum of features which include intrahepatic stones, cholelithiasis, PFIC type 3, and intrahepatic cholestasis of pregnancy. Here, we are reporting a peculiar case of young male adolescent with novel variant compound heterozygote missense mutation in ABCB4 gene who had gall stone as initial symptom, followed by symptoms of PFIC and eventually decompensated chronic liver disease.

scholarly journals Leptin Receptor Compound Heterozygosity in Humans and Animal Models

2021 ◽  
Vol 22 (9) ◽  
pp. 4475
Author(s):  
Claudia Berger ◽  
Nora Klöting
Keyword(s):  
Food Intake ◽  
Animal Models ◽  
Leptin Receptor ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Compound Heterozygosity ◽  
Therapy Options ◽  
Obese Phenotype ◽  
Deficient Mice

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.

scholarly journals Novel compound heterozygous mutation in SACS gene leads to a milder autosomal recessive spastic ataxia of Charlevoix‐Saguenay, ARSACS , in a Finnish family

2016 ◽  
Vol 4 (12) ◽  
pp. 1151-1156 ◽  
Author(s):  
Johanna Palmio ◽  
Mikko Kärppä ◽  
Peter Baumann ◽  
Sini Penttilä ◽  
Jukka Moilanen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Spastic Ataxia
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