Transcriptional Regulation by the Wilms Tumor Protein, Wt1, Suggests a Role of the Metalloproteinase Adamts16 in Murine Genitourinary Development

Jacobi, C. A.; Rudigier, Lucas J.; Scholz, Holger; Kirschner, Karin M.

doi:10.1074/jbc.m113.464644

Cited by 31 publications

(22 citation statements)

References 64 publications

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“…Heterozygous mutant males had a normal migration of their gonads suggesting a recessive feature. Given that Adamts16 is a downstream target of WT1, this study rises suspicion on the role of Adamts16 polymorphisms in cryptorchid men with an otherwise normal function of the WT1 protein …”

Section: Molecular Genetics Of Cryptorchidismmentioning

confidence: 83%

“…Given that Adamts16 is a downstream target of WT1, this study rises suspicion on the role of Adamts16 polymorphisms in cryptorchid men with an otherwise normal function of the WT1 protein. 130 Gene specific deletion of Desrt, a novel murine ARID class DNAbinding protein, causes cryptorchidism. 131 No clinical investigation has been reported so far on any gene variation in patients with cryptorchidism.…”

Section: Other Genetic Causes: Lessons From Animal Modelsmentioning

confidence: 99%

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Molecular genetics of hypospadias and cryptorchidism recent developments

et al. 2018

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During the last decade, a tremendous amount of work has been devoted to the study of the molecular genetics of isolated hypospadias and cryptorchidism, two minor forms of disorders of sex development (DSD). Beyond the genes involved in gonadal determination and sex differentiation, including those underlying androgen biosynthesis and signaling, new genes have been identified through genome-wide association study and familial clustering. Even if no single genetic defect can explain the whole spectrum of DSD, these recent studies reinforce the strong role of the genetic background in the occurrence of these defects. The timing of signaling disruption may explain the different phenotypes.

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Section: Molecular Genetics Of Cryptorchidismmentioning

confidence: 83%

Section: Other Genetic Causes: Lessons From Animal Modelsmentioning

confidence: 99%

Molecular genetics of hypospadias and cryptorchidism recent developments

et al. 2018

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“…Although there were 11 known genes ( LOC340094, ADAMTS16, KIAA0947, FLJ33360, MED10, UBE2QL1, LOC255167, NSUN2, SRD5A1, PAPD7, and MIR4278 ) located in the first deletion in 5p15.33p15.31, only a few of them are fully characterized for gene functions and disease association. Recent whole exome sequencing study revealed that homozygous splicing mutation in NSUN2 to be a cause of Dubowitz-like syndrome, an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies [31]; The ADAMTS16 gene has been reported to play a role of the metalloproteinase in murine genitourinary development [32], and loss-of-function mutations of the MED10 gene have been previously linked with WNT/GSK3β/β-Catenin pathway function [33]. Only SRD5A1 haploinsufficiency has been speculated to be associated with cerebellar hypoplasia, hypospadias, and facial dysmorphisms in a prenatal study [28].…”

Section: Discussionmentioning

confidence: 99%

A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rare Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis

Jiang

et al. 2013

PLoS ONE

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Cri-du-Chat syndrome (MIM 123450) is a chromosomal syndrome characterized by the characteristic features, including cat-like cry and chromosome 5p deletions. We report a family with five individuals showing chromosomal rearrangements involving 5p, resulting from rare maternal complex chromosomal rearrangements (CCRs), diagnosed post- and pre-natally by comprehensive molecular and cytogenetic analyses. Two probands, including a 4½-year-old brother and his 2½-year- old sister, showed no diagnostic cat cry during infancy, but presented with developmental delay, dysmorphic and autistic features. Both patients had an interstitial deletion del(5)(p13.3p15.33) spanning ∼26.22 Mb. The phenotypically normal mother had de novo CCRs involving 11 breakpoints and three chromosomes: ins(11;5) (q23;p14.1p15.31),ins(21;5)(q21;p13.3p14.1),ins(21;5)(q21;p15.31p15.33),inv(7)(p22q32)dn. In addition to these two children, she had three first-trimester miscarriages, two terminations due to the identification of the 5p deletion and one delivery of a phenotypically normal daughter. The unaffected daughter had the maternal ins(11;5) identified prenatally and an identical maternal allele haplotype of 5p. Array CGH did not detect any copy number changes in the mother, and revealed three interstitial deletions within 5p15.33-p13.3, in the unaffected daughter, likely products of the maternal insertions ins(21;5). Chromothripsis has been recently reported as a mechanism drives germline CCRs in pediatric patients with congenital defects. We postulate that the unique CCRs in the phenotypically normal mother could resulted from chromosome 5p chromothripsis, that further resulted in the interstitial 5p deletions in the unaffected daughter. Further high resolution sequencing based analysis is needed to determine whether chromothripsis is also present as a germline structural variation in phenotypically normal individuals in this family.

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“…ADAMTS-16 is a member of the ADAMTS family. Expression of Adamts16 has been reported in rodent fetal lung and kidneys, adult brain and ovaries [3], [4], and most recently in mice embryonic and adult rat gonads [5]. Several studies have implicated ADAMTS16 in various pathological conditions, including osteoarthritis [6], [7], colorectal and esophageal cancers [8], hypertension [9], [10] and physical functional impairment in the context of major mental illnesses including bipolar disorder, major depressive disorder and schizophrenia [11].…”

Section: Introductionmentioning

confidence: 99%

Cryptorchidism and Infertility in Rats with Targeted Disruption of the Adamts16 Locus

et al. 2014

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A Disintegrin And Metalloproteinase with ThromboSpondin motifs16 (ADAMTS-16) is a member of a family of metalloproteinases. Using a novel zinc-finger nuclease based gene-edited rat model harboring a targeted mutation of the Adamts16 locus, we previously reported this gene to be linked to blood pressure regulation. Here we document our observation with this model that Adamts16 is essential for normal development of the testis. Absence of Adamts16 in the homozygous Adamts16mutant males resulted in cryptorchidism and male sterility. Heterozygous Adamts16mutant males were normal, indicating that this is a recessive trait. Testes of homozygous Adamts16mutant males were significantly smaller with significant histological changes associated with the lack of sperm production. Temporal histological assessments of the testis demonstrated that the seminiferous tubules did not support active spermatogenesis, but progressively lost germ cells, accumulated vacuoles and did not have any sperm. These observations, taken together with our previous report of renal abnormalities observed with the same Adamts16mutant rats, suggest an important mechanistic link between Adamts16 and the functioning of the male genitourinary system.

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Transcriptional Regulation by the Wilms Tumor Protein, Wt1, Suggests a Role of the Metalloproteinase Adamts16 in Murine Genitourinary Development

Cited by 31 publications

References 64 publications

Molecular genetics of hypospadias and cryptorchidism recent developments

Molecular genetics of hypospadias and cryptorchidism recent developments

A Familial Cri-du-Chat/5p Deletion Syndrome Resulted from Rare Maternal Complex Chromosomal Rearrangements (CCRs) and/or Possible Chromosome 5p Chromothripsis

Cryptorchidism and Infertility in Rats with Targeted Disruption of the Adamts16 Locus

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