Biallelic loss-of-function variants of GFRA1 cause lethal bilateral renal agenesis

Abstract The genetic causes of multiple congenital anomalies are incompletely understood. Here we report novel heterozygous predicted loss-of-function and predicted damaging missense variants in the WBP11 gene, in seven unrelated families with a variety of overlapping congenital malformations including cardiac, vertebral, tracheo-oesophageal, renal and limb defects. WBP11 encodes a component of the spliceosome with the ability to activate pre-mRNA splicing. We generated a Wbp11 null allele in mouse using CRISPR-Cas9 targeting. Wbp11 homozygous null embryos die prior to E8.5, indicating that Wbp11 is essential for development. Fewer Wbp11 heterozygous null mice are found than expected, due to embryonic and postnatal death. Importantly, Wbp11 heterozygous null mice are small and exhibit defects in axial skeleton, kidneys and oesophagus, similar to the affected individuals, supporting the role of WBP11 haploinsufficiency in the development of congenital malformations in humans. Loss-of-function WBP11 variants should be considered as a possible cause of VACTERL association as well as isolated Klippel-Feil syndrome, renal agenesis or oesophageal atresia.

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SAT-437 NOVEL LOSS OF FUNCTION VARIANTS IN FRAS1 AND FREM2 GENES UNDERLIE RENAL AGENESIS IN CONSANGUINEOUS FAMILIES

Kidney International Reports ◽

10.1016/j.ekir.2020.02.464 ◽

2020 ◽

Vol 5 (3) ◽

pp. S183

Author(s):

M. AL-HAMED

Keyword(s):

Renal Agenesis ◽

Loss Of Function

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A Bi-allelic Frameshift Mutation in NPNT Causes Bilateral Renal Agenesis in Humans

Journal of the American Society of Nephrology ◽

10.1681/asn.2020121762 ◽

2021 ◽

pp. ASN.2020121762

Author(s):

Lei Dai ◽

Jingzhi Li ◽

Liangqun Xie ◽

Weinan Wang ◽

Yang Lu ◽

...

Keyword(s):

Mouse Model ◽

Kidney Development ◽

Renal Agenesis ◽

Genetic Diagnosis ◽

Homozygosity Mapping ◽

Loss Of Function ◽

Fetal Ultrasonography ◽

Whole Exome ◽

Recessive Form

Background: Bilateral renal agenesis (BRA) is a lethal congenital anomaly caused by the failure of normal development of both kidneys early in embryonic development. Oligohydramnios upon fetal ultrasonography reveals BRA. Although exact causes are not clear, BRA is associated with mutations in many renal development genes. However, molecular diagnostics cannot pick up many clinical cases. Nephronectin (NPNT) may be a candidate protein for widening diagnosis. It is essential in kidney development and knockout of Npnt in mice frequently leads to kidney agenesis or hypoplasia. Methods: A consanguineous Han family experienced three cases of induced abortion in the second trimester of pregnancy due to suspicion of BRA. Whole-exome sequencing-(WES)-:based homozygosity mapping detected underlying genetic factors, and a knock-in mouse model confirmed the renal agenesis phenotype. Results: WES and evaluation of homozygous regions in II-3 and II-4 revealed a pathological homozygous frameshift variant in NPNT (NM_001184690:exon8:c.777dup/p.Lys260*), which leads to a premature stop in the next codon. The truncated NPNT protein exhibited decreased expression, as confirmed in vivo by the overexpression of WT and mutated NPNT. A knock-in mouse model homozygous for the detected Npnt mutation replicated the BRA phenotype. Conclusions: A biallelic loss-of-function NPNT mutation causing an autosomal recessive form of BRA in humans was confirmed by the corresponding phenotype of knock-in mice. Our results identify a novel genetic cause of BRA, revealing a new target for genetic diagnosis, prenatal diagnosis, and preimplantation diagnosis for families with BRA.

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Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis

Journal of the American Society of Nephrology ◽

10.1681/asn.2020040478 ◽

2020 ◽

Vol 32 (1) ◽

pp. 223-228

Author(s):

Veronica Arora ◽

Suliman Khan ◽

Ayman W. El-Hattab ◽

Ratna Dua Puri ◽

Maria Eugenia Rocha ◽

...

Keyword(s):

Autosomal Recessive ◽

Renal Agenesis ◽

Genetic Diagnosis ◽

Hirschsprung Disease ◽

Autosomal Recessive Inheritance ◽

Causal Role ◽

Data Repository ◽

Loss Of Function ◽

Genome Data ◽

Fatal Form

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are one of the most common malformations identified in the fetal stage. Bilateral renal agenesis (BRA) represents the most severe and fatal form of CAKUT. Only three genes have been confirmed to have a causal role in humans (ITGA8, GREB1L, and FGF20).MethodsGenome sequencing within a diagnostic setting and combined data repository analysis identified a novel gene.ResultsTwo patients presented with BRA, detected during the prenatal period, without additional recognizable malformations. They had parental consanguinity and similarly affected, deceased siblings, suggesting autosomal recessive inheritance. Evaluation of homozygous regions in patient 1 identified a novel, nonsense variant in GFRA1 (NM_001348097.1:c.676C>T, p.[Arg226*]). We identified 184 patients in our repository with renal agenesis and analyzed their exome/genome data. Of these 184 samples, 36 were from patients who presented with isolated renal agenesis. Two of them had loss-of-function variants in GFRA1. The second patient was homozygous for a frameshift variant (NM_001348097.1:c.1294delA, p.[Thr432Profs*13]). The GFRA1 gene encodes a receptor on the Wolffian duct that regulates ureteric bud outgrowth in the development of a functional renal system, and has a putative role in the pathogenesis of Hirschsprung disease.ConclusionsThese findings strongly support the causal role of GFRA1-inactivating variants for an autosomal recessive, nonsyndromic form of BRA. This knowledge will enable early genetic diagnosis and better genetic counseling for families with BRA.

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Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.38685 ◽

2018 ◽

Vol 176 (7) ◽

pp. 1610-1613 ◽

Cited By ~ 7

Author(s):

Chloé Quélin ◽

Philippe Loget ◽

Lucile Boutaud ◽

Nadia Elkhartoufi ◽

Joelle Milon ◽

...

Keyword(s):

Renal Agenesis ◽

Loss Of Function

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Nephron progenitor maintenance is controlled through FGFs and Sprouty1 Interaction

10.1101/2020.03.26.010421 ◽

2020 ◽

Author(s):

Sung-Ho Huh ◽

Ligyeom Ha ◽

Hee-Seong Jang

Keyword(s):

Cell Death ◽

Tyrosine Kinases ◽

Kidney Development ◽

Renal Agenesis ◽

Treatment Strategies ◽

Loss Of Function ◽

Nephron Progenitors ◽

Novel Treatment Strategies ◽

Nephron Progenitor ◽

Progenitor Maintenance

AbstractThe nephron progenitor cells (NPCs) give rise to all segments of functional nephrons and are of great interest due to their potential as a source for novel treatment strategies for kidney disease. Fibroblast growth factor (FGF) signal plays pivotal roles in generating and maintaining NPCs during kidney development. However, molecule(s) regulating FGF signal during nephron development is not known. Sprouty (SPRY) is an antagonist of receptor tyrosine kinases. During kidney development, SPRY1 is expressed in the ureteric buds (UBs) and regulates UB branching by antagonizing Ret-GDNF signal. Here, we provide evidence that SPRY1 expressed in NPCs modulates activity of FGF signal in NPCs and regulates NPC stemness. Haploinsufficiency of Spry1 rescues bilateral renal agenesis and premature NPC differentiation caused by loss of Fgf9 and Fgf20. In addition, haploinsufficiency of Spry1 rescues NPC proliferation and cell death defects induced by loss of Fgf9 and Fgf20. In the absence of SPRY1, FGF9 and FGF20, another FGF ligand, FGF8 promotes nephrogenesis. Deleting both Fgf8 and Fgf20 results in kidney agenesis and defects in NPC proliferation and cell death. Rescue of loss of Fgf9 and Fgf20 induced renal agenesis by Spry1 haploinsufficiency was reversed when one copy of Fgf8 was deleted. These findings indicate the importance of the balance between positive and negative signal during NPC maintenance. Failure of the balance may underlie some human congenital kidney malformation.Significance StatementNephrons are functional units of kidney to filter blood to excrete wastes and regulate osmolarity and ion concentrations. Nephrons are derived from nephron progenitors. Nephron progenitors are depleted during kidney development which makes it unable to regenerate nephrons. Therefore, understanding signaling molecules regulating nephron progenitor generation and maintenance is of great interest for the future kidney regenerative medicine. Here, we show that Sprouty1 regulates nephron progenitor maintenance by inhibiting FGF signal. Deletion of Sprouty1 rescues renal agenesis and nephron progenitor depletion in the Fgf9/20 loss-of-function kidneys. Further decrease of FGF signal by deleting one copy of Fgf8 makes kidneys irresponsive to Sprouty1 resulting in failure of nephron progenitor maintenance. This study thus identifies the reciprocal function of FGF-Sprouty1 signal during nephron progenitor development.

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E3 ubiquitin ligases

Essays in Biochemistry ◽

10.1042/bse0410015 ◽

2005 ◽

Vol 41 ◽

pp. 15-30 ◽

Cited By ~ 123

Author(s):

Helen C. Ardley ◽

Philip A. Robinson

Keyword(s):

Protein Complexes ◽

Loss Of Function ◽

Direct Role ◽

Cellular Processes ◽

Substrate Protein ◽

Protein Ubiquitination ◽

C Terminus ◽

Full Complement ◽

Spatio Temporal ◽

Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

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Metallic prions

Biochemical Society Symposium ◽

10.1042/bss0710193 ◽

2004 ◽

Vol 71 ◽

pp. 193-202 ◽

Cited By ~ 9

Author(s):

David R Brown

Keyword(s):

Prion Protein ◽

Binding Capacity ◽

Normal Function ◽

Transmissible Spongiform Encephalopathies ◽

Published Data ◽

Normal Brain ◽

Copper Binding ◽

Loss Of Function ◽

Spongiform Encephalopathies ◽

The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

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Errata

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2008.marapr02 ◽

2008 ◽

Vol 13 (2) ◽

pp. 5-5

Keyword(s):

Psychotic Disorders ◽

Pain Syndrome ◽

Vestibular Disorders ◽

Loss Of Function ◽

Sixth Edition ◽

Neurologic Disorders ◽

Upper And Lower Extremities ◽

Impairment Ratings ◽

Extensive List ◽

Mental And Behavioral Disorders

Abstract Although most chapters in the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), Sixth Edition, instruct evaluators to perform impairment ratings by first assigning a diagnosis-based class and then assigning a grade within that class, Chapter 13, The Central and Peripheral Nervous System, continues to use a methodology similar to that of the fifth edition. The latter was criticized for duplicating materials that were presented in other chapters and for producing different ratings, so the revision of Chapter 13 attempts to maintain consistency between this chapter and those that address mental and behavioral disorders, loss of function in upper and lower extremities, loss of bowel control, and bladder and sexual function. A table titled Summary of Chapters Used to Rate Various Neurologic Disorders directs physicians to the relevant chapters (ie, instead of Chapter 13) to consult in rating neurologic disorders; the extensive list of conditions that should be addressed in other chapters includes but is not limited to radiculopathy, plexus injuries and other plexopathies, focal neuropathy, complex regional pain syndrome, visual and vestibular disorders, and a range of primary mood, anxiety, and psychotic disorders. The article comments in detail on sections of this chapter, identifies changes in the sixth edition, and provide guidance regarding use of the new edition, resulting in less duplication and greater consistency.

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