Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure

Katari, Sunita; Wood-Trageser, Michelle A.; Jiang, Huaiyang; Kalynchuk, Eve Justine; Muzumdar, Radhika; Yatsenko, Svetlana A.; Rajkovic, Aleksander

doi:10.1210/jc.2015-1401

Cited by 51 publications

(26 citation statements)

References 10 publications

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“…Furthermore, the wild-type residue is very conserved and located near a highly conserved position in the TMD as observed in previously described mutations [Doherty et al, 2002;Katari et al, 2015;Bramble et al, 2016].…”

Section: Discussionsupporting

confidence: 59%

“…Recently, 2 novel FSHR mutations in 2 unrelated POF cohorts were identified using WES. Both mutations (c.1253T>G;p.Ile418Ser and c.1222G>T;p.Asp408Tyr) are also located in exon 10 in the highly conserved second TMD [Katari et al, 2015;Bramble et al, 2016]. Moreover, a nearby pathogenic variant (c.1255G>A;p.Ala419Thr) was detected in a Finnish female with primary amenorrhea.…”

Section: Discussionmentioning

confidence: 99%

“…Our novel c.1298C>A;p.Ala433Asp homozygous FSHR variant was also detected by massively parallel exome sequencing as well as the variants c.1253T>G; p.Ile418Ser and c.1222G>T;p.Asp408Tyr recently identified [Katari et al, 2015;Bramble et al, 2016]. WES deeply screens all coding regions and allows for the identification of mutations in patients with rare genetic disorders.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

França

Lerário

Funari

et al. 2017

Sex Dev

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Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46,XX girl and a 46,XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c.1298C>A;p.Ala433Asp missense variant of the follicle-stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/EVS) and Brazilian exome controls. Moreover, it is highly conserved and predicted as deleterious in all prediction sites analyzed. In conclusion, the novel homozygous FSHR variant observed in 2 siblings with HH can expand the spectrum of FSHR mutations in humans.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

França

Lerário

Funari

et al. 2017

Sex Dev

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“…Nup107 (c.1066C>T, p.R355C) variant was investigated further by introducing it in the mouse. Mice are good models for human reproductive tract disease, and replicate the human phenotype of HH for many genes studies such as Fshr and Sohlh1 (Dierich et al., ; Aittomaki et al., ; Katari et al., ; Bayram et al., ). Missense variants, which result in single or few nucleotide changes that convert one amino acid to another are much more common, but more difficult to functionally assess.…”

Section: Resultsmentioning

confidence: 99%

Functional study of a novel missense single‐nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency

Ren

Diao

Katari

et al. 2018

Molec Gen & Gen Med

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BackgroundHypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant.MethodsWe performed a high‐resolution X‐chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9.ResultsWhole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C>T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility.ConclusionsOur findings indicate that NUP107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility.

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“…The analysis of a few cohorts of 46,XX POI patients by means of high throughput techniques, such as comparative genomic hybridization array (array-CGH) and SNP array, has led to the identification of CNVs affecting several X-linked and autosomal loci with a possible role in female fertility (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Similarly, the recent application of whole-exome sequencing (WES) to a few POI multigenerational familial cases has succeeded in revealing rare single nucleotide variants affecting genes implicated in ovarian function (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). As already reported in other complex diseases characterized by a great genetic heterogeneity, it is likely that patients with POI may harbor multiple genetic variants.…”

Section: The Heterogeneous Manifestations and Multifactorial Origin Omentioning

confidence: 99%

Genetics of primary ovarian insufficiency

et al. 2016

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Primary ovarian insufficiency (POI) is characterized by a loss of ovarian function before the age of 40 and account for one major cause of female infertility. POI relevance is continuously growing because of the increasing number of women desiring conception beyond 30 years of age, when POI prevalence is >1%. POI is highly heterogeneous and can present with ovarian dysgenesis and primary amenorrhea, or with secondary amenorrhea, and it can be associated with other congenital or acquired abnormalities. In most cases POI remains classified as idiopathic. However, the age of menopause is an inheritable trait and POI has a strong genetic component. This is confirmed by the existence of several candidate genes, experimental and natural models. The variable expressivity of POI defect may indicate that, this disease may frequently be considered as a multifactorial or oligogenic defect. The most common genetic contributors to POI are the X chromosome‐linked defects. Here, we review the principal X‐linked and autosomal genes involved in syndromic and non‐syndromic forms of POI with the expectation that this list will soon be upgraded, thus allowing the possibility to predict the risk of an early age at menopause in families with POI.

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Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure

Cited by 51 publications

References 10 publications

A Novel Homozygous Missense <b><i>FSHR</i></b> Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

A Novel Homozygous Missense <b><i>FSHR</i></b> Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

Functional study of a novel missense single‐nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency

Genetics of primary ovarian insufficiency

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