No abstract

Non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), and microhomology-mediated replication-dependent recombination (MMRDR) have all been put forward as mechanisms to explain DNA rearrangements associated with genomic disorders. However, many nonrecurrent rearrangements in humans remain unexplained. To further investigate the mutation mechanisms of these copy number variations (CNVs), we performed breakpoint mapping analysis for 62 clinical cases with intragenic deletions in the human DMD gene (50 cases) and other known diseasecausing genes (one PCCB, one IVD, one DBT, three PAH, one STK11, one HEXB, three DBT, one HRPT1, and one EMD cases). While repetitive elements were found in only four individual cases, three involving DMD and one HEXB gene, microhomologies (2-10 bp) were observed at breakpoint junctions in 56% and insertions ranging from 1 to 48 bp were seen in 16 of the total 62 cases. Among these insertions, we observed evidence for tandem repetitions of short segments (5-20 bp) of reference sequence proximal to the breakpoints in six individual DMD cases (six repeats in one, four repeats in three, two repeats in one, and one repeat in one case), strongly indicating attempts by the replication machinery to surpass the stalled replication fork. We provide evidence of a novel template slippage event during replication rescue. With a deeper insight into the complex process of replication and its rescue during origin failure, brought forward by recent studies, we propose a hypothesis based on aberrant firing of replication origins to explain intragenic nonrecurrent rearrangements within genes, including the DMD gene.

Acute kidney injury (AKI) has been associated with deleterious impacts on a variety of body systems. While AKI is often accompanied by dysregulation of mineral metabolism—including alterations in calcium, phosphate, vitamin D, parathyroid hormone, fibroblast growth factor 23, and klotho—its direct effects on the skeletal system of children and adolescents remain largely unexplored. In this review, the pathophysiology of dysregulated mineral metabolism in AKI and its potential effects on skeletal health are discussed, including data associating AKI with fracture risk.

Baker et al. 7 82 (77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87) 87 (85-90) 64 (58-69) 95 (93-96) USRDS 6 74 (69-80) 91 (89-93) 69 (63-76) 93 (91-94) CureGN þ Sahli et al. 89 (85-93) 93 (91-95) 78 (73-83) 97 (96-98) CureGN þ USRDS 91 (87-95) 88 (86-90) 68 (63-74) 97 (96-98) CureGN þ Sahli et al. þ Baker et al. 93 (90-96) 83 (80-85) 60 (55-65) 98 (97-99) CureGN þ Sahli et al. þ Baker et al. þ USRDS 94 (90-97) 79 (76-82) 56 (51-61) 98 (97-99) Validation phase CureGN þ Sahli et al. 75 (61-89) 91 (84-99) 87 (75-99) 83 (72-93) CI, confidence interval; ICD-10, International Classification of Diseases, Tenth Revision; NPV, negative predictive value; PPV, positive predictive value; USRDS, United States Renal Data System. aThe 95% confidence intervals were calculated using the Wald method.