Urogenital and caudal dysgenesis in adrenocortical dysplasia ( acd ) mice is caused by a splicing mutation in a novel telomeric regulator

Keegan, Catherine E.; Hutz, Janna; Else, Tobias; Adamska, Maja; Shah, S.; Kent, Amy E.; Howes, John M.; Beamer, Wesley G.; Hammer, Gary D.

doi:10.1093/hmg/ddi011

Cited by 63 publications

(100 citation statements)

References 48 publications

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Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

“…To assess the role of Acd in hematopoiesis, we first used mice that were homozygous for the spontaneously occurring hypomorphic acd allele (30). This allele was originally described to cause adrenocortical dysplasia and was thus named acd (30). It is characterized by a G to A transition within the third intron ( Figure 1A), resulting in aberrant splicing and either a 7-bp insertion after exon 3 or inclusion of the third intron in the mRNA (30,35).…”

Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

“…This allele was originally described to cause adrenocortical dysplasia and was thus named acd (30). It is characterized by a G to A transition within the third intron ( Figure 1A), resulting in aberrant splicing and either a 7-bp insertion after exon 3 or inclusion of the third intron in the mRNA (30,35). Both outcomes cause premature termination of translation and a truncated protein lacking all functional domains.…”

Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

“…As HSC loss leading to bone marrow failure is the most frequent cause of lethality in DKC, understanding the importance of telomerase and shelterin genes in hematopoiesis is relevant to human disease. Mice deficient for Acd due to homozygosity for a spontaneously arising hypomorphic acd allele demonstrate a pleiotrophic phenotype that includes adrenocortical dysplasia, caudal truncation, genitourinary abnormalities, skin hyperpigmentation, and substantial strain-dependent embryonic or perinatal lethality (30). These data indicate the tissue-specific functions of TPP1.…”

Section: Introductionmentioning

confidence: 85%

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Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Jones¹,

Osawa²,

Regal³

et al. 2013

J. Clin. Invest.

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The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors.

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Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

See 2 more Smart Citations

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Jones¹,

Osawa²,

Regal³

et al. 2013

J. Clin. Invest.

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“…In mice, the adrenocortical dysplasia (acd) mutant phenotype, caused by a hypomorphic allele of Tpp1, includes a number of features of DC, including growth retardation, skin hyperpigmentation, and sparse hair (Keegan et al 2005). In addition, mouse hematopoietic stem cells Ribbon view of structural model of K170Δ generated using the wild-type structure as a template.…”

Section: Discussionmentioning

confidence: 99%

Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

et al. 2014

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Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-aminoacid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.

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Exome sequencing identifies variants in infants with sacral agenesis

Pitsava

Feldkamp

Pankratz

et al. 2022

Birth Defects Research

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Background Sacral agenesis (SA) consists of partial or complete absence of the caudal end of the spine and often presents with additional birth defects. Several studies have examined gene variants for syndromic forms of SA, but only one has examined exomes of children with non‐syndromic SA. Methods Using buccal cell specimens from families of children with non‐syndromic SA, exomes of 28 child–parent trios (eight with and 20 without a maternal diagnosis of pregestational diabetes) and two child–father duos (neither with diagnosis of maternal pregestational diabetes) were exome sequenced. Results Three children had heterozygous missense variants in ID1 (Inhibitor of DNA Binding 1), with CADD scores >20 (top 1% of deleterious variants in the genome); two children inherited the variant from their fathers and one from the child's mother. Rare missense variants were also detected in PDZD2 (PDZ Domain Containing 2; N = 1) and SPTBN5 (Spectrin Beta, Non‐erythrocytic 5; N = 2), two genes previously suggested to be associated with SA etiology. Examination of variants with autosomal recessive and X‐linked recessive inheritance identified five and two missense variants, respectively. Compound heterozygous variants were identified in several genes. In addition, 12 de novo variants were identified, all in different genes in different children. Conclusions To our knowledge, this is the first study reporting a possible association between ID1 and non‐syndromic SA. Although maternal pregestational diabetes has been strongly associated with SA, the missense variants in ID1 identified in two of three children were paternally inherited. These findings add to the knowledge of gene variants associated with non‐syndromic SA and provide data for future studies.

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Urogenital and caudal dysgenesis in adrenocortical dysplasia ( acd ) mice is caused by a splicing mutation in a novel telomeric regulator

Cited by 63 publications

References 48 publications

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

Exome sequencing identifies variants in infants with sacral agenesis

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