The novel contiguous gene syndrome of myotubular myopathy (MTM1), male hypogenitalism and deletion in Xq28:report of  the first familial case

Bartsch, Oliver; Kreß, Wolfram; Wagner, Andrew; Seemanová, E

doi:10.1159/000015284

Cited by 35 publications

(23 citation statements)

References 15 publications

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“…In this regard, although the mouse homolog for CXorf6 is not expressed in the adult testis, it is clearly expressed in the adult ovary (3) where SF1 (4,5) and HES3 are also expressed. In addition, premature ovarian failure has been described in a female with heterozygosity for a microdeletion involving CXorf6 (34). Thus, CXorf6 and its possible interaction with SF1 and HES3 may also be relevant to adult ovarian function.…”

Section: Discussionmentioning

confidence: 99%

Mastermind-like Domain-containing 1 (MAMLD1 or CXorf6) Transactivates the Hes3 Promoter, Augments Testosterone Production, and Contains the SF1 Target Sequence

Fukami

Wada

Okada

et al. 2008

Journal of Biological Chemistry

106

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Although chromosome X open reading frame 6 (CXorf6) has been shown to be a causative gene for hypospadias, its molecular function remains unknown. To clarify this, we first examined CXorf6 protein structure, identifying homology to mastermindlike 2 (MAML2) protein, which functions as a co-activator in canonical Notch signaling. Transactivation analysis for wildtype CXorf6 protein by luciferase assays showed that CXorf6 significantly transactivated the promoter of a noncanonical Notch target gene hairy/enhancer of split 3 (Hes3) without demonstrable DNA-binding capacity. Transactivation analysis was also performed for the previously described three apparently pathologic nonsense mutations, indicating that E124X and Q197X proteins had no transactivation function, whereas R653X protein retained a nearly normal transactivation function. Subcellular localization analysis revealed that wild-type and R653X proteins co-localized with MAML2 protein in nuclear bodies, whereas E124X and Q197X proteins were incapable of localizing to nuclear bodies. Thus, further studies were performed for R653X, revealing the occurrence of nonsense mediated mRNA decay in vivo. Next, transient knockdown of CXorf6 was performed using small interfering RNA, showing reduced testosterone production in mouse Leydig tumor cells. Furthermore, steroidogenic factor 1 (SF1) protein bound to a specific sequence in the upstream of the CXorf6 coding region and exerted a transactivation activity. These results suggest that CXorf6 transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence, thereby providing the first clue to clarify the biological role of CXorf6. We designate CXorf6 as MAMLD1 (mastermind-like domaincontaining 1) based on its characteristic structure.

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Section: Discussionmentioning

confidence: 99%

Mastermind-like Domain-containing 1 (MAMLD1 or CXorf6) Transactivates the Hes3 Promoter, Augments Testosterone Production, and Contains the SF1 Target Sequence

Fukami

Wada

Okada

et al. 2008

Journal of Biological Chemistry

106

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“…A gene for 46,XY DSD has been postulated around MTM1 for myotubular myopathy on Xq28, on the basis of the finding that genital development is normal in patients with intragenic MTM1 mutations, and invariably abnormal in 6 patients with microdeletions involving MTM1 [10,11,12,13]. The 6 patients consist of 3 sporadic and 3 familial cases, and 5 of them have glandular, penile, or penoscrotal hypospadias and the remaining 1 patient exhibits ambiguous genitalia [10,11,12].…”

Section: Cloning Of a Candidate Gene For 46xy Dsdmentioning

confidence: 99%

“…The 6 patients consist of 3 sporadic and 3 familial cases, and 5 of them have glandular, penile, or penoscrotal hypospadias and the remaining 1 patient exhibits ambiguous genitalia [10,11,12]. These findings suggest that a gene for 46,XY DSD, especially that for hypospadias, resides in the vicinity of MTM1 , and that loss or disruption of the gene results in the development of 46,XY DSD as consequence of a contiguous gene deletion syndrome.…”

Section: Cloning Of a Candidate Gene For 46xy Dsdmentioning

confidence: 99%

<i>MAMLD1 (CXorf6):</i> A New Gene Involved in Hypospadias

Ogata¹,

Laporte²,

Fukami³

2009

Horm Res Paediatr

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MAMLD1 (mastermind-like domain containing 1), previously known as CXorf6 (chromosome X open reading frame 6), has been shown to be a causative gene for hypospadias. This is primarily based on the identification of nonsense mutations (E124X, Q197X, and R653X), which undergo nonsense-mediated mRNA decay, in patients with penoscrotal hypospadias. Subsequent studies have shown that (1) the mouse homolog is transiently expressed in fetal Sertoli and Leydig cells around the critical period of sex development; (2) transient knockdown of Mamld1 results in significantly reduced testosterone production in murine Leydig tumor cells; (3) MAMLD1 protein shares homology to mastermind-like 2 (MAML2) protein that functions as a co-activator in canonical Notch signaling; (4) MAMLD1 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3 (Hes3), rather than the canonical Notch target genes such as Hes1 and Hes5, without demonstrable DNA-binding capacity, and (5) MAMLD1 is regulated by steroidogenic factor 1. These findings suggest that the MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period of sex development, and provide useful information for the molecular network involved in fetal testosterone production.

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“…It is also hypothesized to be implicated in male genital development. Indeed, myopathic individuals with intragenic mutations of MTM1 have normal sexual development, whereas those with microdeletions of MTM1 extending to the CXorf6 locus have abnormal genitalia (8)(9)(10)(11). Subsequent studies have demonstrated that CXorf6 is mutated in 46,XY disorders of sexual development (46,XY DSD): Fukami et al (12) have identified three nonsense mutations in four individuals with 46,XY DSD including micropenis, bifid scrotum, and penoscrotal hypospadias.…”

Section: Introductionmentioning

confidence: 99%

Mutations of CXorf6 are associated with a range of severities of hypospadias

Kalfa

Liu

Klein

et al. 2008

European Journal of Endocrinology

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Objective: Mutations in chromosome X open reading frame 6 (CXorf6), a recently described candidate gene involved in the development of male genitalia, have been found in patients with complex 46,XYdisorders of sexual development (46,XY DSD) including micropenis, bifid scrotum, and penoscrotal hypospadias. The objective of this work was to identify genomic variants of CXorf6 in patients with isolated hypospadias, severe or non-severe. Design and methods: Forty-one patients with glandular to perineal hypospadias and thirty controls were studied. Direct sequencing for coding exons 3-6 of CXorf6 and their flanking splice sites was performed on DNA extracted from foreskin collected from surgery. Secondary and tertiary structures of the protein were predicted using NNpredict and Protein Homology/analogY Recognition Engine engines. Results: Four mutations (9.7% of cases) were identified. One missense mutation (1295TOC, V432A) and two deletions (325delG, predicted to cause a stop codon L121X) occurred in patients with penoscrotal and proximal hypospadias. One patient with subcoronal hypospadias had CAG-repeat amplification in the second polyglutamine domain of CXorf6. Secondary structure prediction indicated that this insertion occurred in a helix element of the protein. The tertiary structure prediction showed an alteration of the shape of the protein and crowding between domains. Conclusion: CXorf6 mutations are associated with isolated hypospadias of varying severity. However, the pathophysiology of these mutations and the function of the CXorf6 gene product remain to be investigated. European Journal of Endocrinology 159 453-458

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The novel contiguous gene syndrome of myotubular myopathy (MTM1), male hypogenitalism and deletion in Xq28:report of the first familial case

Cited by 35 publications

References 15 publications

Mastermind-like Domain-containing 1 (MAMLD1 or CXorf6) Transactivates the Hes3 Promoter, Augments Testosterone Production, and Contains the SF1 Target Sequence

Mastermind-like Domain-containing 1 (MAMLD1 or CXorf6) Transactivates the Hes3 Promoter, Augments Testosterone Production, and Contains the SF1 Target Sequence

<i>MAMLD1 (CXorf6):</i> A New Gene Involved in Hypospadias

Mutations of CXorf6 are associated with a range of severities of hypospadias

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