An additional type of male sterility and inherited urinary obstruction in mice with thet-haplotypeth7

Lyon, Mary F.

doi:10.1017/s0016672300033735

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…Because T is expressed throughout the notochord, it is possible for the phenotypic manifestation of a mutation to occur anywhere along the vertebral column. Indeed, in mice, T mutations affect not only the tail but also more anterior vertebral segments,

^{(^{(26,27)})}

spinal cord,

^{(^{(26,28)})}

genitourinary system,

^{(^{(26,29)})}

and heart.

^{(^{(30,31)})}

Other investigators have reported the association of a C to T transition in intron 7 of T and increased risk of neural tube defects,

^{(^{(32–34)})}

but this finding has not been uniformly reproduced.

^{(^{(35–37)})}

Thus, the potential range of mutant T phenotypes must be broadened to include neural tube defects, as well as CVMs. Moreover, it is desirable to account for the absence of a clinical phenotype in the unaffected parents of our three c.1013C>T CVM subjects.…”

Section: Discussionmentioning

confidence: 99%

A Missense T(Brachyury) Mutation Contributes to Vertebral Malformations

Ghebranious

Blank

Raggio

et al. 2008

Journal of Bone and Mineral Research

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ABSTRACT:No major susceptibility genes for sporadically occurring congenital vertebral malformations (CVM) in humans have been identified to date. Body patterning genes whose mutants cause axial skeletal anomalies in mice are candidates for human CVM susceptibility. T (also known as Brachyury) and TBX6 are critical genes needed to establish mesodermal identity. We hypothesized that mutations in T and/or TBX6 contribute to the pathogenesis of human CVMs. The complete T and TBX6 coding regions, splice junctions, and proximal 500 bp of the promoters were sequenced in 50 phenotyped patients with CVM. Three unrelated patients with sacral agenesis, Klippel-Feil syndrome, and multiple cervical and thoracic vertebral malformations were heterozygous for a c.1013C>T substitution, resulting in a predicted Ala338Val missense alteration in exon 8. A clinically unaffected parent of each patient also harbored the substitution, but the variant did not occur in an ethnically diverse, 443-person reference population. The c.1013C>T variant is significantly associated with CVM (p < 0.001). Alanine 338 shows moderate conservation across species, and valine at this position has not been reported in any species. A fourth patient harbored a c.908-8C>T variant in intron 7. This previously unreported variant was tested in 347 normal control subjects, and 11 heterozygotes and 2 T/T individuals were found. No TBX6 variants were identified. We infer that the c.1013C>T substitution is pathogenic and represents the first report of an association between a missense mutation in the T gene and the occurrence of sporadic CVMs in humans. It is uncertain whether the splice junction variant increases CVM risk. TBX6 mutations do not seem to be associated with CVM. We hypothesize that epistatic interactions between T and other developmental genes and the environment modulate the phenotypic consequences of T variants.

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^{(^{(26,27)})}

spinal cord,

^{(^{(26,28)})}

genitourinary system,

^{(^{(26,29)})}

and heart.

^{(^{(30,31)})}

Other investigators have reported the association of a C to T transition in intron 7 of T and increased risk of neural tube defects,

^{(^{(32–34)})}

but this finding has not been uniformly reproduced.

^{(^{(35–37)})}

Section: Discussionmentioning

confidence: 99%

A Missense T(Brachyury) Mutation Contributes to Vertebral Malformations

Ghebranious

Blank

Raggio

et al. 2008

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…Since expression of T is distributed throughout the notochord, it is possible for the phenotypic manifestation of a mutation to occur anywhere along the vertebral column. This is exemplified by the observation that T mutations in mice affect not only the tail, but also more anterior vertebral segments, 124,125 spinal cord, 124,126 genitourinary system, 124,127 and heart 128,129 . An association between a C to T transition in intron 7 of T and increased risk of neural tube defects 130–132 has been reported by some investigators, but this finding has not been uniformly reproduced 133–135 .…”

Section: Klippel−feil Syndromementioning

confidence: 99%

Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans

Giampietro

Dunwoodie

Kusumi

et al. 2008

Annals of the New York Academy of Sciences

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Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement, and functional distress. This review explores (1) recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation; and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and nonsyndromic congenital vertebral malformation. Discussion includes exploration of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation, and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families.

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“…Therefore, alterations in methylation may significantly affect embryonic development (Rogers et al, 1994). Evidence of the genetic role in growth and reproductive development has been described (Lyon, 1996) and influence of heredity on body size has been reported (de Table 3-5-AZA-2′-Deoxycytidine F1 reproductive parameters (3 months of age) Castro, 1993). In addition, maternal factors play a role in the development of the exaggerated appetite for some specific nutrients (Erkadius et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

5‐AZA‐2′‐deoxycytidine (5‐AZA‐CdR): a demethylating agent affecting development and reproductive capacity

Cisneros

Branch

2003

J of Applied Toxicology

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The objective was to evaluate the effects of 5-AZA-2'-deoxycytidine (5-AZA-CdR) on postnatal development and reproductive capacity. Pregnant mice were administered 1 mg kg-1 5-AZA-CdR at gestation day 10. The body weights of F1 control and treated (in uterine-exposed) pups were recorded. To evaluate the reproductive capacity, 5-AZA-CdR F1 males and females were mated with control mice. The presence of plugs and the number of pregnancies were recorded. The 5-AZA-CdR F1 male mice were killed. Total body, testes and epididymis weights were recorded. Spermatid head counting, histological analyses and serum testosterone levels were performed. Body weights of 5-AZA-CdR F1 mice were statistically lower than controls (P < 0.01), with the females more strongly affected (P < 0.05). Male mating capacity appeared to be more adversely affected. Mating of 5-AZA-CdR F1 males with control females resulted in a lower pregnancy rate compared with control mating groups (P < 0.01). Gross testicular and epididymis weights were lower in 5-AZA-CdR F1 mice (P < 0.01). However, testicular and epididymis weights in these mice were higher than controls when correlated to body weight (P < 0.01). In 5-AZA-CdR F1 male mice, all measured reproductive parameters, including total number of spermatid heads per testis, are significantly lower (P < 0.01) than the controls except for the number of spermatid heads per milligram of testis.

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An additional type of male sterility and inherited urinary obstruction in mice with thet-haplotypet^h7

Cited by 7 publications

References 27 publications

A Missense T(Brachyury) Mutation Contributes to Vertebral Malformations

A Missense T(Brachyury) Mutation Contributes to Vertebral Malformations

Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans

5‐AZA‐2′‐deoxycytidine (5‐AZA‐CdR): a demethylating agent affecting development and reproductive capacity

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