XY sex reversal associated with a deletion 5' to the SRY "HMG box" in the testis-determining region.

McElreavy, Kenneth; Vilain, Éric; Abbas, Nacer; Costa, Jean‐Marc; Souleyreau, N.; Kucheria, Kiran; Boucekkine, C.; Thibaud, E; Brauner, Raja; Flamant, Frédéric

doi:10.1073/pnas.89.22.11016

Cited by 167 publications

(84 citation statements)

References 28 publications

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“…There is considerable evidence that the testis-determination factor a 35 kb sequence is located adjacent to the pseudoautosomal boundary of the Y chromosome. It is well documented that the SR Y-gene encodes a factor that is necessary for the initiation of testis-development Goodfellow and Darling, 1988;Hawkins et al, 1992;Koopman et al, 1991;McElreavy et al, 1992;Sinclair et al, 1990). It is possible that the direct insertion of Y euchromatin material at band q21.2 of the X chromosome is related to the presence of hypogonadotropic hypogonadism in this case.…”

Section: Resultsmentioning

confidence: 72%

Direct insertion of euchromatic material from chromosome y in the x-chromosome in hypogonadotropic hypogonadisms with crohn’s disease

1997

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SummaryThe relationship between chromosomal abnormalities and Crohn's disease has not been established. Crohn's disease is associated with inflammation of the bowel, severe abdominal pain and chronic diarrhea. Its etiology is not known at present. A recessive gene with incomplete penetrance is thought to be a factor which does not follow simple mendelian inheritance. We report a case, where the euchromatin material of Y chromosome (pl 1.1 pl 1.2) has been directly inserted into the long arm of the X chromosome (q21.2), and is assumed to be the most likely cause of hypogonadotropic hypogonadism in this patient. It could also be that the function of the testis-determining factor (SR Y) has been disrupted due to the insertion, causing loss of testicular development.

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Section: Resultsmentioning

confidence: 72%

Direct insertion of euchromatic material from chromosome y in the x-chromosome in hypogonadotropic hypogonadisms with crohn’s disease

1997

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“…To date, 29 unique missense and nonsense mutations of the SRY gene have been reported in XY female patients (Fig. 2) (Hawkins et al 1992a;Hawkins et al 1992b;McElreavy et al 1992a, McElreavy et al 1992bMuller et al 1992;Affara et al 1993;Jager et al 1993;Hawkins 1993;Schmitt-Ney et al 1993;Zeng et al 1993;Iida et al 1994;Poulat et al 1994;Tajima et al 1994;Hiort et al 1995;Bilbao et al 1996;Cameron and Sinclair 1997;Veitia et al 1997;Brown et al 1998;Domenice et al 1998;Scherer et al 1998). Most of these mutations are located within the HMG box domain in the SRY gene, which has a sequence-specific DNA-binding activity.…”

Section: Discussionmentioning

confidence: 99%

A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal

et al. 2000

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BRIEF REPORT -MUTATION REPORT known as the HMG box, possesses sequence-specific DNAbinding activity and acts as a transcriptional regulator in the cascade of sex determination (Gubbay et al. 1990). The XY female is rare and is characterized by sexual infantilism, the absence of differentiated gonads (only streak gonads being present), and the presence of normally developed Mullerian structures, including uterus and fallopian tubes, in a phenotypic female with an XY karyotype. Approximately 15% of XY female phenotype patients harbor nonsense or missense mutations and deletion mutations of the SRY gene, which are mainly present within the HMG box (Hawkins et al. 1992a;Ferguson-Smith 1992). We experienced a phenotypic female patient presenting with abdominal tumor; molecular analysis identified a novel missense mutation within the HMG box of the SRY gene. Patient and methods Case historyA 12-year-old phenotypic female was referred to the Pediatric Department at Hokkaido University Hospital because of a right lower abdominal mass. She was 153 cm tall (ϩ0.65 SD for normal Japanese female) and her weight was 35.9 kg. She was born to healthy unrelated parents and had had an uneventful gestation period. She had been healthy until this visit, when an abdominal mass was observed. She had not manifested any secondary sexual characteristics at that time.On examination, a 20 ϫ 18-cm firm mass was palpated in the lower abdomen. The patients pubertal stage was B1, PH1 according to the Tanner stage. Abdominal computed tomography detected a right gonadal mass of 18 ϫ 11 ϫ 7 cm, a left streak gonad, and prepubertal-size uterus. Endocrinological examination demonstrated extremely elevated basal plasma levels of follicle-stimulating hormone (24.8 mIU/ml; standard range for prepubertal teen-aged girl, 1.16-3.65 mIU/ml) and luteinizing hormone (143.0 mIU/ml; standard range for prepubertal teen-aged Abstract The sex-determining region of the Y chromosome, the SRY gene, located on the short arm of the Y chromosome, is appreciated as one of the genes that is responsible for directing the process of sex differentiation. To date, 34 different mutations, including 29 missense and nonsense mutations in the SRY gene, have been described in XY female patients. We investigated the molecular basis of the sex reversal in one Japanese XY female patient by determining the nucleotide sequence of the SRY gene, using polymerase chain reaction and direct sequencing. We identified a novel mutation, of the substitution of Tyr for Asn at nucleotide position 87 (N87Y). This Asn residue is located within the DNA-binding high-mobility-group (HMG) motif, which is considered to be the main functional domain of the SRY protein. Further, this amino acid, Asn, is a conserved residue among mammalian SRY genes. These findings indicate that this amino acid substitution may be responsible for the sex reversal in this patient.

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“…Na sín-drome de Swyer (mulheres XY), somente 20% apresentam mutação no gene SRY. Até 1996, 18 pacientes com disgenesia gonadal 46,XY apresentavam mutação no quadro de leitura do SRY (13)(14)(15). Mais de 10 tipos de mutações têm sido encontradas no SRY e, exceto deleções 5' no quadro de leitura do SRY, todas as outras caem no interior da região que codifica a proteína HMG.…”

Section: O Fator De Determinação Testicular (Tdf)unclassified

O enigma da determinação gonadal: o que existe além do cromossomo Y?

Damiani

Dichtchekenian

Setian

2000

Arq Bras Endocrinol Metab

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RESUMOOs autores revisam os vários fatores envolvidos no complexo processo de determinação gonadal, passando pelo já clássico SRY (fator de determinação testicular, no braço curto do cromossomo Y) e ressaltando os principais genes candidatos a participarem desta verdadeira "cascata" de determinação gonadal. Os genes candidatos se avolumam e têm mostrado os vários caminhos por que passa o processo-chave da diferenciação sexual, qual seja, a diferenciação de um testículo ou de um ovário. Genes localizados upstream em relação ao SRY (WT1, SF-1, DAX-1 e SOX9), suas interdependências e a ativação de promotores de outros genes, como o promotor do gene do hormônio anti-mülleriano são abordados neste artigo. Apesar de a lista de genes candidatos ter crescido, ainda restam muitas interrogações e ainda resta muito trabalho a ser desenvolvido para que se esclareça com maior precisão este passo crucial no mecanismo de diferenciação sexual. ABSTRACTThis paper reviews the many steps involved in the complex process of gonadal differentiation, starting with the already "classic" SRY (sex-determining region on the Y chromosome) and highlighting the main candidate genes to this "cascade" of sexual determination. The number of candidate genes has grown showing the complexity involved in the path from a bipotential gonad to reach its destiny as a testis or as an ovary. We discuss the interdependency of the genes located upstream of SRY, such as WT1, SF-1, DAX-1, and SOX9, and how one gene can activate the promoter of other genes in the process (SF-1 + WT1 activate the promoter of AMH). Although the list of candidate genes has increased, many questions remain unanswered and a lot of work is still needed to clarify this complex step of sexual differentiation, namely, gonadal determination. abordando aspectos da endocrinologia fetal em relação aos hormônios gonadais e hipofisários, bem como seus clássicos estudos sobre o efeito da castração de coelhos e sua repercussão na diferenciação sexual, muito se tem aprendido a respeito do evento-chave da diferenciação sexual, qual seja, a transformação da gônada bipotencial em testículo ou em ovário.O interesse científico a respeito dos mecanismos de determinação sexual vem dos tempos de Aristóteles (384-322 AC). Em 355 AC, Aristóteles postulava que o dimorfismo sexual surgia de diferenças na tem-

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XY sex reversal associated with a deletion 5' to the SRY "HMG box" in the testis-determining region.

Cited by 167 publications

References 28 publications

Direct insertion of euchromatic material from chromosome y in the x-chromosome in hypogonadotropic hypogonadisms with crohn’s disease

Direct insertion of euchromatic material from chromosome y in the x-chromosome in hypogonadotropic hypogonadisms with crohn’s disease

A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal

O enigma da determinação gonadal: o que existe além do cromossomo Y?

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