Pallister‐Hall syndrome, <scp>GLI3</scp>, and kidney malformation

McClelland, Kathryn S.; Li, Weili; Rosenblum, Norman D.

doi:10.1002/ajmg.c.31999

Cited by 6 publications

(5 citation statements)

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“…Alterations of the SHH signaling pathway have been implicated in both developmental and degenerative instances of kidney disease, such as nephronophthisis [ 21 , 22 ] and kidney fibrosis [ 23 ], supporting a role for disease modification [ 24 ]. A specific example is Pallister-Hall syndrome (MIM #146510) where genetic alterations of GLI3, a transcriptional effector in the SHH signaling pathway, lead to developmental defects of multiple organ systems including uni- and bilateral CAKUT [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome

Sewerin,

Aurnhammer,

Skubic

et al. 2023

Clinical Kidney Journal

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Background Branchiootorenal (BOR) syndrome is an autosomal dominant disorder caused by pathogenic EYA1 variants and clinically characterized by auricular malformations with hearing loss, branchial arch anomalies, and congenital anomalies of the kidney and urinary tract (CAKUT). BOR phenotypes are highly variable and heterogenous. While random monoallelic expression is assumed to explain this phenotypic heterogeneity, the potential role of modifier genes has not yet been explored. Methods Through thorough phenotyping and exome sequencing, we studied one family with disease presentation in at least four generations in both clinical and genetic terms. Functional investigation of the single associated EYA1 variant c.1698+1G>A included splice site analysis and assessment of EYA1 distribution in patient-derived fibroblasts. The candidate modifier gene CYP51A1 was evaluated by histopathological analysis of murine CYP51A1+/− kidneys. As the gene encodes the enzyme Lanosterol 14α-demethylase, we assessed sterol intermediates in patient blood samples as well. Results The EYA1 variant c.1698+1G>A resulted in functional deletion of the EYA domain by exon skipping. The EYA domain mediates protein-protein interactions between EYA1 and co-regulators of transcription. EYA1 abundance was reduced in the nuclear compartment of patient-derived fibroblasts, suggesting impaired nuclear translocation of these protein complexes. Within the affected family, renal phenotypes spanned from normal kidney function in adulthood to chronic kidney failure in infancy. By analyzing exome sequencing data for variants segregating with an effect on the kidney, we identified a canonical splice site alteration in CYP51A1 as the strongest candidate variant, potentially playing a role as genetic modifier. Conclusions In this study, we demonstrate pathogenicity of EYA1 c.1698+1G>A, propose a mechanism for dysfunction of mutant EYA1, and conjecture CYP51A1 as a potential genetic modifier of renal involvement in BOR syndrome.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome

Sewerin,

Aurnhammer,

Skubic

et al. 2023

Clinical Kidney Journal

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“…Although all PHS-causing GLI3 variants are predicted to generate GLI3R-like transcripts, only a quarter of PHS patients present with CAKUT. region of the GLI3 gene, and found no correlation between locus of mutagenesis and prevalence of (72). It may be, however, that the spectrum of renal phenotypes found in PHS patients is mediated by GLI3 variant-specific mechanisms that are difficult to elucidate from genotype alone.…”

Section: Gli3mentioning

confidence: 94%

“…A diagnosis of Pallister-Hall Syndrome is met upon the criteria of hypothalamic hamartoma, mesoaxial polydactyly, and a confirmed mutation in the central-third of the GLI3 gene ( 68 – 71 ). PHS is characterized by a further spectrum of multi-organ malformations, including CAKUT ( 71 , 72 ). An estimated 27% of PHS patients present with CAKUT, with hypoplasia (with or without dysplasia) and agenesis being most common (accounting for just under one third of PHS cases with CAKUT, each).…”

Section: Hh Signaling In Human Kidney Developmentmentioning

confidence: 99%

“…Other types of CAKUT found in PHS include dysplasia, ectopic kidney, single kidney, and VUR, all of which are reported to occur unilaterally and bilaterally at equal frequency. PHS patients with CAKUT are more likely to experience craniofacial defects, bifid epiglottis, and genital hypoplasia ( 72 ).…”

Section: Hh Signaling In Human Kidney Developmentmentioning

confidence: 99%

“…A recent patient cohort study by McClelland et al. investigated the link between GLI3 variants and renal phenotype in PHS patients; the study demonstrated that PHS-causing GLI3 variants are evenly distributed within the central third region of the GLI3 gene, and found no correlation between locus of mutagenesis and prevalence of CAKUT ( 72 ). It may be, however, that the spectrum of renal phenotypes found in PHS patients is mediated by GLI3 variant-specific mechanisms that are difficult to elucidate from genotype alone.…”

Section: Hh Signaling In Human Kidney Developmentmentioning

confidence: 99%

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Hedgehog-GLI mediated control of renal formation and malformation

et al. 2023

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CAKUT is the leading cause of end-stage kidney disease in children and comprises a broad spectrum of phenotypic abnormalities in kidney and ureter development. Molecular mechanisms underlying the pathogenesis of CAKUT have been elucidated in genetic models, predominantly in the mouse, a paradigm for human renal development. Hedgehog (Hh) signaling is critical to normal embryogenesis, including kidney development. Hh signaling mediates the physiological development of the ureter and stroma and has adverse pathophysiological effects on the metanephric mesenchyme, ureteric, and nephrogenic lineages. Further, disruption of Hh signaling is causative of numerous human developmental disorders associated with renal malformation; Pallister-Hall Syndrome (PHS) is characterized by a diverse spectrum of malformations including CAKUT and caused by truncating variants in the middle-third of the Hh signaling effector GLI3. Here, we outline the roles of Hh signaling in regulating murine kidney development, and review human variants in Hh signaling genes in patients with renal malformation.

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The genetic etiologies of bilateral renal agenesis

Kirschen,

Blakemore,

Al‐Kouatly

et al. 2024

Prenatal Diagnosis

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ObjectiveThe goal of this study was to review and analyze the medical literature for cases of prenatal and/or postnatally diagnosed bilateral renal agenesis (BRA) and create a comprehensive summary of the genetic etiologies known to be associated with this condition.MethodsA literature search was conducted as a scoping review employing Online Mendeliain Inheritance in Man, PubMed, and Cochrane to identify cases of BRA with known underlying genetic (chromosomal vs. single gene) etiologies and those described in syndromes without any known genetic etiology. The cases were further categorized as isolated versus non‐isolated, describing additional findings reported prenatally, postnatally, and postmortem. Inheritance pattern was also documented when appropriate in addition to the reported timing of diagnosis and sex.ResultsWe identified six cytogenetic abnormalities and 21 genes responsible for 20 single gene disorders associated with BRA. Five genes have been reported to associate with BRA without other renal anomalies; sixteen others associate with both BRA as well as unilateral renal agenesis. Six clinically recognized syndromes/associations were identified with an unknown underlying genetic etiology. Genetic etiologies of BRA are often phenotypically expressed as other urogenital anomalies as well as complex multi‐system syndromes.ConclusionMultiple genetic etiologies of BRA have been described, including cytogenetic abnormalities and monogenic syndromes. The current era of the utilization of exome and genome‐wide sequencing is likely to significantly expand our understanding of the underlying genetic architecture of BRA.

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Pallister‐Hall syndrome, GLI3, and kidney malformation

Cited by 6 publications

References 50 publications

Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome

Mechanisms of pathogenicity and the quest for genetic modifiers of kidney disease in branchiootorenal syndrome

Hedgehog-GLI mediated control of renal formation and malformation

The genetic etiologies of bilateral renal agenesis

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