Deletions in Xq28 in Two Boys with Myotubular Myopathy and Abnormal Genital Development Define a New Contiguous Gene Syndrome in a 430 kb Region

Hu, Ling-Jia; Laporte, Jocelyn; Kreß, Wolfram; Kioschis, Petra; Siebenhaar, Renate; Poustka, Annemarie; Fardeau, Michel; Metzenberg, Aı̈da; Janssen, Emiel A. M.; Thomas, Nick; Mandel, Jean Louis; Dahl, Niklas

doi:10.1093/hmg/5.1.139

Cited by 65 publications

(61 citation statements)

References 19 publications

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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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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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“…1 The locus responsible for the disease (MTM1) was mapped to proximal Xq28 by linkage analysis and the candidate region was restricted by analysing recombination events and patients carrying deletions. 2,3 We have recently reported the identification of the MTM1 gene by positional cloning. 4 It encodes a protein (myotubularin) with a putative tyrosine phosphatase domain (PTP).…”

Section: Introductionmentioning

confidence: 99%

“…Four cosmids (ICRF C104-H05147, C104-E03147, C104-B03151 and a Xq28 specific library cosmid Qc3A3) were subcloned as described. 3 Subclones were screened by hybridisation with radioactively labelled cDNAs or oligonucleotides, and by PCR, for the presence of MTM1 exons and further sequenced with exon specific primers. As exons 5 to 8 were not included in our cosmid contig, PCR and long-range PCR from genomic DNA was performed with exonic primers, to clone introns 4, 5, 6, 7 and 8.…”

Section: Introductionmentioning

confidence: 99%

“…Exon 1 is present in cosmid Qc3A3 from a Xq28 library, while exon 2 is present in the overlapping cosmid C104-B03151 from Lawrence Livermore National Laboratories. 3 A polymorphic CA repeat was characterised in the putative promoter sequence at position -2624 to -2587 of the sequence in Figure 2. Briefly, 100 ng of patient DNA were amplified in 10 mM tris-HCl pH 8.3, 50 mM KCl, 200 µM dNTP, 1.5 mM MgCl 2 , with 10 pmoles of each primers, 1 nmole (3 µCi) of 32 P dCTP and 1 unit of Taq polymerase in a total volume of 25 µl.…”

Section: Introductionmentioning

confidence: 99%

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Genomic organization of the MTM1 gene implicated in X-linked myotubular myopathy

et al. 1998

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X-linked recessive myotubular myopathy (XLMTM) is a very severe congenital muscular disease characterised by an impaired maturation of muscle fibres, and caused by defects in the MTM1 gene. This gene defines a new family of putative tyrosine phosphatases conserved through evolution. We have determined intronic flanking sequences for all the 15 exons to facilitate the detection of mutations in patients and genetic counselling. We characterised a new polymorphic marker in the immediate vicinity of the gene, which might prove useful for linkage analysis. Sequencing of the TATA-less predicted promoter provides the basis for transcriptional regulatory studies.

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“…Large deletions including part or the entire upstream MAMLD1 gene cause a contiguous gene syndrome with hypospadias and myotubular myopathy in males. 13 A duplication of exon 10 has been recently described in an affected male. 14 DNM2: Thirteen heterozygous missense changes or in-frame deletions or insertions have been reported with hotspots at position 368, 369, 465, 522, 618 and 619.…”

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confidence: 99%