Genomic Characterization of the Inherited Bone Marrow Failure Syndromes

Khincha, Payal P.; Savage, Sharon A.

doi:10.1053/j.seminhematol.2013.09.002

Cited by 65 publications

(65 citation statements)

References 99 publications

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“…Such cases along with clinical suspicion necessitate additional testing of fibroblasts obtained through skin biopsy. 6,7 The vast majority of FA patients present in childhood when hematopoietic disease, be it bone marrow failure or acute myeloid leukemia, predominates. The key treatment of such patients has been stem cell transplantation (SCT).…”

Section: Clinical Features Of Famentioning

confidence: 99%

Stress and DNA repair biology of the Fanconi anemia pathway

Longerich

Xiong

et al. 2014

Blood

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Fanconi anemia (FA) represents a paradigm of rare genetic diseases, where the quest for cause and cure has led to seminal discoveries in cancer biology. Although a total of 16 FA genes have been identified thus far, the biochemical function of many of the FA proteins remains to be elucidated. FA is rare, yet the fact that 5 FA genes are in fact familial breast cancer genes and FA gene mutations are found frequently in sporadic cancers suggest wider applicability in hematopoiesis and oncology. Establishing the interaction network involving the FA proteins and their associated partners has revealed an intersection of FA with several DNA repair pathways, including homologous recombination, DNA mismatch repair, nucleotide excision repair, and translesion DNA synthesis. Importantly, recent studies have shown a major involvement of the FA pathway in the tolerance of reactive aldehydes. Moreover, despite improved outcomes in stem cell transplantation in the treatment of FA, many challenges remain in patient care. (Blood.

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Section: Clinical Features Of Famentioning

confidence: 99%

Stress and DNA repair biology of the Fanconi anemia pathway

Longerich

Xiong

et al. 2014

Blood

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“…Approximately 75% to 90% of SDS patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene (7)(8)(9). Since the identification of SBDS in 2003, only 2 other causal SDS genes, DNAJC21 (10,11) and EFL1 (12), have been reported, in contrast to other IBMFSs, for which the situation is the opposite (e.g., >20 loci in Fanconi anemia, >10 loci in Diamond-Blackfan anemia, and several loci in severe congenital neutropenia) (13).…”

Section: Introductionmentioning

confidence: 99%

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

Carapito¹,

Konantz²,

Paillard³

et al. 2017

Journal of Clinical Investigation

134

145

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Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. Using trio whole-exome sequencing (WES) in an SBDS-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in SRP54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.

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“…35 In addition, mice homozygously expressing a p53 truncation mutant, p53 D31 -which lacks the C-terminal negative regulatory domain -develop dyskeratosis congenita, a syndrome characterized by nail dystrophy, oral leukoplakia, skin hyperpigmentation, aplastic anemia, and pulmonary fibrosis and attributable to telomerase dysfunction and consequent telomere attrition. 67,68 A direct role for p53 in triggering phenotypes upon telomere erosion is indicated by studies in telomerasedeficient mice, where germ cell depletion is partially rescued by p53 loss. 69 While telomere attrition clearly induces DNA damage, thereby activating p53, some effects may also be through ribosome biogenesis defects, as telomere maintenance proteins are also required for processing of rRNAs.…”

Section: The Role Of P53 In Other Diseasesmentioning

confidence: 99%