Familial Syndrome of Streak Gonads and Normal Male Karyotype in Five Phenotypic Females

Espiner, Eric A.; Veale, A. M. O.; Sands, Valerie E.; Fitzgerald, P. H.

doi:10.1056/nejm197007022830102

Cited by 107 publications

(21 citation statements)

References 28 publications

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“…Linkage analysis in this family placed the mutated locus on the pericentric region of chromosome 5 [11]. Recently, we attributed the cause of 46,XY GD in this, and a second family [12], to mutations in the gene encoding the signal transduction molecule, MAP3K1 [13]. Two sporadic cases of 46,XY GD were also reported to harbour MAP3K1 mutations.…”

Section: Introductionmentioning

confidence: 83%

Minor Abnormalities of Testis Development in Mice Lacking the Gene Encoding the MAPK Signalling Component, MAP3K1

Warr¹,

Bogani²,

Siggers³

et al. 2011

PLoS ONE

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In mammals, the Y chromosome is a dominant male determinant, causing the bipotential gonad to develop as a testis. Recently, cases of familial and spontaneous 46,XY disorders of sex development (DSD) have been attributed to mutations in the human gene encoding mitogen-activated protein kinase kinase kinase 1, MAP3K1, a component of the mitogen-activated protein kinase (MAPK) signal transduction pathway. In individuals harbouring heterozygous mutations in MAP3K1, dysregulation of MAPK signalling was observed in lymphoblastoid cell lines, suggesting a causal role for these mutations in disrupting XY sexual development. Mice lacking the cognate gene, Map3k1, are viable and exhibit the eyes open at birth (EOB) phenotype on a mixed genetic background, but on the C57BL/6J genetic background most mice die at around 14.5 dpc due to a failure of erythropoiesis in the fetal liver. However, no systematic examination of sexual development in Map3k1-deficient mice has been described, an omission that is especially relevant in the case of C57BL/6J, a genetic background that is sensitized to disruptions to testis determination. Here, we report that on a mixed genetic background mice lacking Map3k1 are fertile and exhibit no overt abnormalities of testis development. On C57BL/6J, significant non-viability is observed with very few animals surviving to adulthood. However, an examination of development in Map3k1-deficient XY embryos on this genetic background revealed no significant defects in testis determination, although minor abnormalities were observed, including an increase in gonadal length. Based on these observations, we conclude that MAP3K1 is not required for mouse testis determination. We discuss the significance of these data for the functional interpretation of sex-reversing MAP3K1 mutations in humans.

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Section: Introductionmentioning

confidence: 83%

Minor Abnormalities of Testis Development in Mice Lacking the Gene Encoding the MAPK Signalling Component, MAP3K1

Warr¹,

Bogani²,

Siggers³

et al. 2011

PLoS ONE

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show abstract

“…For instance, Cohen and Shaw (1965) have described the XY-type of pure gonadal dysgenesis in brothers and sisters, Sternberg, Barclay, and Kloepfer (1968) in cousins, and Frasier, Bashore, and Mosier (1964) in twins. Espiner et al (1970) gave an account of a family in which five phenotypically female members were affected. This form of gonadal dysgenesis is inherited in a manner similar to that of testicular feminization, that is by means of an autosomal dominant or a recessive sex-linked gene.…”

Section: Discussionmentioning

confidence: 99%

Clinical variations of testicular intersexuality in a family

Gardó

Papp

1974

Journal of Medical Genetics

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“…The TDF gene is considered to be the trigger that initiates testicular determination. However, at least one gene on the X chromosome also plays a role in testicular determination [Bernstein et al, 1970;Espiner et al, 1970;German et al, 19781, and there is evidence that several autosomal genes are also necessary [Hall et al, 1980;Gessler et al, 19891. The TDF gene has been localized to the distal region of the short arm of the Y chromosome near the pseudoautosomal boundary [Rosenfeld et al, 1979;Magenis et al, 1984;Disteche et al, 1986;Muller et al, 1986;Page et al, 1987;Affara et al, 1987;Levilliers et al, 19891.…”

Section: Discussionmentioning

confidence: 99%

Partial gonadal dysgenesis in a patient with a marker Y chromosome

et al. 1992

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We evaluated a patient with partial gonadal dysgenesis including a right dysgenetic testis and a left streak gonad with rudimentary fallopian tube and uterus. She had ambiguous external genitalia and was raised female. Although her height is normal (25th centile at age 12 years), she has some findings of Ullrich-Turner syndrome. Her karyotype was reported to be 46,X,+marker; subsequent molecular investigations showed the marker to be the short arm of the Y chromosome. Genomic DNA, isolated from leukocytes of the patient and her father, was digested with a variety of restriction endonucleases and subjected to Southern blot analysis. A positive hybridization signal was obtained with probes for the short arm of the Y chromosome (pRsY0.55, SRY, ZFY, 47Z, pY-190, and YC-2) in DNA from the patient, indicating the presence of most if not all of the short arm, while long arm probes (HinfA and pY3.4) indicated that at least 75% of the long arm of the Y chromosome was missing. The gene responsible for testicular determination (TDF) is on the distal portion of the short arm of the Y chromosome; Yq has no known influence on sex determination. Hence, the deletion of the long arm of the Y chromosome cannot explain the gonadal dysgenesis in this patient. One explanation for the gonadal dysgenesis and Ullrich-Turner phenotype in the patient could be undetected 45,X/46,X,+marY mosaicism but no such mosaicism was observed in peripheral lymphocytes. Several investigators have suggested the presence of an "anti-Turner" gene near TDF. Hence it is possible that the clinical phenotype in our patient results from a Y chromosomal defect in sequences flanking TDF, which reduces the function of both TDF and the "anti-Turner" genes.

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Familial Syndrome of Streak Gonads and Normal Male Karyotype in Five Phenotypic Females

Cited by 107 publications

References 28 publications

Minor Abnormalities of Testis Development in Mice Lacking the Gene Encoding the MAPK Signalling Component, MAP3K1

Minor Abnormalities of Testis Development in Mice Lacking the Gene Encoding the MAPK Signalling Component, MAP3K1

Clinical variations of testicular intersexuality in a family

Partial gonadal dysgenesis in a patient with a marker Y chromosome

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