Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46,XY disorder of sex development

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically female patient with pubertal delay had a 46,XY karyotype and was diagnosed with 46,XY disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower-molecular-weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46,XY DSD illustrates how different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.

Download Full-text

Identification by array-Comparative Genomic Hybridization (array-CGH) of a large deletion of luteinizing hormone receptor gene combined with a missense mutation in a patient diagnosed with a 46,XY disorder of sex development and application to prenatal diagnosis

Endocrine Journal ◽

10.1507/endocrj.k11e-119 ◽

2011 ◽

Vol 58 (9) ◽

pp. 769-776 ◽

Cited By ~ 10

Author(s):

Nicolas Richard ◽

Céline Leprince ◽

Nicolas Gruchy ◽

Pascal Pigny ◽

Joris Andrieux ◽

...

Keyword(s):

Array Comparative Genomic Hybridization ◽

Array Cgh ◽

Receptor Gene ◽

Large Deletion ◽

Luteinizing Hormone Receptor ◽

Comparative Genomic ◽

Comparative Genomic Hybridization Array ◽

Disorder Of Sex Development ◽

Sex Development ◽

Hormone Receptor Gene

Download Full-text

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

10.21203/rs.3.rs-1148926/v1 ◽

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.

Download Full-text

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

10.21203/rs.3.rs-786500/v1 ◽

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.

Download Full-text

Anti-Myelin Oligodendrocyte Glycoprotein Encephalomyelitis and Extensive Longitudinal Transverse Myelitis Associated with Compound Heterozygous NLRP3 Missense Mutations in a Young Child

Journal of Pediatric Neurology ◽

10.1055/s-0040-1721434 ◽

2020 ◽

Author(s):

Deirdre O'Sullivan ◽

Michael Moore ◽

Susan Byrne ◽

Andreas O. Reiff ◽

Susanna Felsenstein

Keyword(s):

Young Child ◽

Genetic Basis ◽

Transverse Myelitis ◽

Acute Disseminated Encephalomyelitis ◽

Myelin Oligodendrocyte Glycoprotein ◽

Compound Heterozygous ◽

Missense Mutations ◽

Childhood Onset

AbstractAcute disseminated encephalomyelitis in association with extensive longitudinal transverse myelitis is reported in a young child with positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody with heterozygous NLRP3 missense mutations; p.(Arg488Lys) and p.(Ser159Ile). This case may well present an exceptional coincidence, but may describe a yet unrecognized feature of the spectrum of childhood onset cryopyrinopathies that contribute to the understanding of the genetic basis for anti-MOG antibody positive encephalomyelitis. Based on this observation, a larger scale study investigating the role of NLRP3 and other inflammasomes in this entity would provide important pathophysiological insights and potentially novel avenues for treatment.

Download Full-text

Cytogenetic and molecular diagnosis of Fanconi anemia revealed two hidden phenotypes: Disorder of sex development and cerebro‐oculo‐facio‐skeletal syndrome

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.694 ◽

2019 ◽

Vol 7 (7) ◽

Author(s):

Abir Ben Haj Ali ◽

Ahlem Amouri ◽

Marwa Sayeb ◽

Saloua Makni ◽

Wajih Hammami ◽

...

Keyword(s):

Molecular Diagnosis ◽

Fanconi Anemia ◽

Disorder Of Sex Development ◽

Sex Development

Download Full-text

The REG1 Gene Product Is Required for Repression of INO1 and Other Inositol-Sensitive Upstream Activating Sequence-Containing Genes of Yeast

Genetics ◽

10.1093/genetics/152.1.89 ◽

1999 ◽

Vol 152 (1) ◽

pp. 89-100 ◽

Cited By ~ 1

Author(s):

Qian Ouyang ◽

Monica Ruiz-Noriega ◽

Susan A Henry

Keyword(s):

Regulatory Protein ◽

Deletion Mutation ◽

Negative Regulator ◽

Regulatory Subunit ◽

Bhlh Protein ◽

Gene Products ◽

Glucose Response ◽

Upstream Activating Sequence ◽

Missense Mutant ◽

Single Base Pair

Abstract A search was conducted for suppressors of the inositol auxotrophic phenotype of the ino4-8 mutant of yeast. The ino4-8 mutation is a single base pair change that results in substitution of lysine for glutamic acid at position 79 in the bHLH domain of the yeast regulatory protein, Ino4p. Ino4p dimerizes with a second bHLH protein, Ino2p, to form a complex that binds to the promoter of the INO1 gene, activating transcription. Of 31 recessive suppressors of ino4-8 isolated, 29 proved to be alleles of a single locus, identified as REG1, which encodes a regulatory subunit of a protein phosphatase involved in the glucose response pathway. The suppressor mutation, sia1-1, identified as an allele of REG1, caused constitutive INO1 expression and was capable of suppressing the inositol auxotrophy of a second ino4 missense mutant, ino4-26, as well as ino2-419, a missense mutation of INO2. The suppressors analyzed were unable to suppress ino2 and ino4 null mutations, but the reg1 deletion mutation could suppress ino4-8. A deletion mutation in the OPI1 negative regulator was incapable of suppressing ino4-8. The relative roles of the OPI1 and REG1 gene products in control of INO1 expression are discussed.

Download Full-text