Polymorphism of 3′ UTR of MAMLD1 gene is also associated with increased risk of isolated hypospadias in Indian children: a preliminary report

Ratan, Simmi K.; Sharma, Anju; Kapoor, Seema; Polipalli, Sunil Kumar; Dubey, Divya; Mishra, Tarun; Sinha, Shandip Kumar; Agarwal, S. K.

doi:10.1007/s00383-016-3856-7

Cited by 11 publications

(9 citation statements)

References 37 publications

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“…The mastermind-like domain-containing 1 ( MAMLD1 ) gene, previously known as Chromosome X open reading frame 6 ( CXorf6 ) or F18 (OMIM# 300120), was first identified in two patients with myotubular myopathy and male hypogenitalism, who were found to harbour a deletion on chromosome Xq28 [ 4 , 5 ]. Although MAMLD1 is 70 kilobase long and contains 12 exons, only 7 of them have been validated to date [ 6 ]. Owing to in-frame alternative splicing, exons 3–6 encode two proteins of 701 and 660 amino acids, respectively, depending on whether the transcript includes or excludes exon 4.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature

Fan

et al. 2020

Orphanet J Rare Dis

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Background: Mastermind-like domain-containing 1 (MAMLD1) has previously been identified as a causative gene for "46,XY Disorders of Sex Development (DSD)". Recently, there has been some controversy regarding the causative role of MAMLD1 variations in DSDs. Here we describe a clinical series and review the reported cases to evaluate the role of MAMLD1 variants in children with 46,XY DSD. Cases of 46,XY DSD harbouring MAMLD1 variants from unrelated families were recruited from the Beijing Children's Hospital in China (N = 10) or identified through a literature search (N = 26). The clinical manifestations and genetic variants of all the patients were evaluated. Results: Hypospadias was the most prevalent phenotype among our 10 cases (8 out of 10 cases) and in all the previously reported ones. Central precocious puberty and isolated micropenis were observed for the first time. Among the 10 cases, nine variants were identified, including three nonsense (p.R356X, p.Q152X, and p.Q124X) and six missense (p.P334S, p.S662R, p.A421P,p.T992I, p.P542S, and p.R927L) variants. In silico analysis showed that the variants p.P334S, p.P542S, p.S662R, and p.R927Lmight lead to drastic changes in the interaction force of the amino acid chain and the flexibility of the spatial structure, and such changes may affect protein function. Conclusion: Patients with 46,XY DSD harbouring MAMLD1variants manifest a broad spectrum of phenotypes and mostly present with hypospadias. The six novel variants reported here enrich the mutation database and contribute to our understanding of the pathogenesis of 46,XY DSD.

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Section: Introductionmentioning

confidence: 99%

Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature

Fan

et al. 2020

Orphanet J Rare Dis

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“…Geller et al, (Geller et al 2014), has been tested on hypospadias cases and control, and identified 18 genomic regions showing independent association with P < 5 × Kappa (DGKK6) which showed differential genetic association with hypospadias risk, positive in Caucasians and negative in the Chinese population. Indian reports have also shown significant association between SRD5A2-V89L (Samtani et al 2011), SRD5A2-A49T, R227Q and TA repeat gene polymorphisms (Samtani et al 2015) and MAMLD1 (c.2960C>T) (Ratan et al 2016) with hypospadias risk and also the severity of the disease. Hence, till date, few genetic associations have been reported in Indian studies but no comprehensive approach has been followed to assess the genetic involvement of different SNPs contributing to pathways like sex hormone biosynthesis and metabolism; embryonic development and Phospholipase D signaling with the severity of Hypospadias.…”

Section: Discussionmentioning

confidence: 92%

Single-nucleotide and Copy-number variance related to severity of Hypospadias

Singh

Gupta

Sharma

et al. 2018

Preprint

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The genetic association of Hypospadias-risk studies has been conducted in Caucasians, Chinese-Han populations and few in Indian populations. Although no comprehensive approach has been followed to assess genetic involvement in the severity of the disorder. The study evaluated to establish the correlation between genotyped SNPs/CNVs and Hypospadias-severity by an association in a total 30 SNPs in genes related to sex hormone-biosynthesis and metabolism; embryonic-development and Phospholipase-D-signalling pathways on 138 surgeryconfirmed hypospadias-cases from North-India (84 Penile and 28 cases of Penoscrotal-Hypospadias compared against 31 cases of Glanular+Coronal), and analyzed and identified copy number variants (CNVs) in four Familial samples (18 members) and three paired-sporadic cases (6 samples) using array-based comparative-genomic-hybridization and validated in 32 Hypospadias samples by TaqMan assay. Based on Odds Ratio at 95% CI, Z Statistic and Significance Levels, STS gene-rs17268974 was associated with Penile-Hypospadias and 9-SNPs (seven-SNPs (rs5934740; rs5934842; rs5934913; rs6639811; rs3923341; rs17268974; rs5934937) of STS gene; rs7562326-SRD5A2 and rs1877031-STARD3 were associated with Penoscrotal-Hypospadias. On aggregate analysis with p <0.001, we identified homozygous-loss of Ch7:q34 (PRSS3P2, PRSS2). On validation in previously CNV-characterized and new (32hypospadias-cases), we identified PRSS3P2-loss in most of the grade 3 and 4 hypospadias. Hence, Grade 1 and 2 (coronal and granular) show no-PRSS3P2-loss and noassociation with SNPs in STS; SRD5A2; STARD3-gene but Grade 3 and 4 (Penile and Penoscrotal) show PRSS3P2-loss accompanied with the association of SNPs in STS; SRD5A2; STARD3. Hence, homozygous-loss of PRSS3P2 accompanied with the association of STS; SRD5A2; STARD3 may link to the severity of the disease.4

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“…There are few reports on LH levels in patients with normal testosterone (at different ages), which are as follows: low-normal range LH (1), normal (low range) LH but increased LH after hCG stimulation (1,8), and normal LH (high range) (15). Furthermore, a comparative study of testosterone and LH levels between MAMLD1-hypospadias patients and control individuals of the same age gave statistically significant differences only in the 4-to 8-year-old group and not at lower ages (28).…”

Section: Discussionmentioning

confidence: 96%

A New MAMLD1 Variant in an Infant With Microphallus and Hypospadias With Hormonal Pattern Suggesting Partial Hypogonadotropic Hypogonadism—Case Report

et al. 2022

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MAMLD1 (X chromosome) is one of the recognized genes related to different sex development. It is expressed in testis and ovaries and seems to be involved in fetal sex development and in adult reproductive function, including testosterone biosynthesis. However, its exact role remains unclear. Over 40 genetic variants have been described, mainly in male individuals and mostly associated with hypospadias. Although MAMLD1 has been shown to regulate the expression of the steroidogenic pathway, patients with MAMLD1 variants mostly show normal gonadal function and normal testosterone levels. Here we describe a patient (46,XY) with hypospadias and microphallus, with low testosterone and dihydrotestosterone (DHT) levels, and with inappropriately low values of luteinizing hormone (LH) during minipuberty. This hormonal pattern was suggestive of partial hypogonadotropic hypogonadism. A stimulation test with hCG (4 months) showed no significant increase in both testosterone and dihydrotestosterone concentrations. At 5 months of age, he was treated with intramuscular testosterone, and the penis length increased to 3.5 cm. The treatment was stopped at 6 months of age. Our gonadal function massive-sequencing panel detected a previously unreported nonsense variant in the MAMLD1 gene (c.1738C>T:p.Gln580Ter), which was classified as pathogenic. This MAMLD1 variant, predicting a truncated protein, could explain his genital phenotype. His hormonal profile (low testosterone, dihydrotestosterone, and LH concentrations) together with no significant increase of testosterone and DHT plasma concentrations (hCG test) highlight the potential role of this gene in the biosynthesis of testosterone during the fetal stage and minipuberty of the infant. Besides this, the LH values may suggest an involvement of MAMLD1 in the LH axis or a possible oligogenesis. It is the first time that a decrease in DHT has been described in a patient with an abnormal MAMLD1.

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Polymorphism of 3′ UTR of MAMLD1 gene is also associated with increased risk of isolated hypospadias in Indian children: a preliminary report

Abstract: Occurrence of MAMDL1 gene polymorphisms, specially of c.2960C>T in 3' UTR of its exon 7 is associated with a higher risk of IH in Indian children, probably by lowering androgenic levels.

Cited by 11 publications

References 37 publications

Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature

Clinical and molecular spectrum of 46,XY disorders of sex development that harbour MAMLD1 variations: case series and review of literature

Single-nucleotide and Copy-number variance related to severity of Hypospadias

A New MAMLD1 Variant in an Infant With Microphallus and Hypospadias With Hormonal Pattern Suggesting Partial Hypogonadotropic Hypogonadism—Case Report

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