Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy

Aypek, Hande; Lu, Shun; Liu, Shuya; Kylies, Dominik; Kretz, Oliver; Wu, Guochao; Moritz, Manuela; Amann, Kerstin; Benz, Kerstin; Tong, Ping; Hu, Zhengmao; Alsulaiman, Sulaiman M.; Khan, Arif O.; Grohmann, Maik; Wagner, Timo; Müller-Deile, Janina; Schlüter, Hartmut; Puelles, Victor G.; Bergmann, Carsten; Huber, Tobias B.; Grahammer, Florian

doi:10.1172/jci147253

Cited by 17 publications

(15 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, a recent study suggests MCP-1 as a biomarker of renal decline in AS patients [ 27 , 56 ]. In closing, we mention a recent elegant work in which they studied a Col4a3 knockout mouse (such as the Col4a3 tm1Jhm ) together with a new Col4a5 knockout model (deletion of exon 36, obtained from the International Mouse Knockout Consortium) [ 57 ]. Both models are in the C57BL/6N strain.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, we should mention a most recent mouse model created to recapitulate thin basement membrane nephropathy caused by null mutations in the prolyl 3-hydroxylase 2 ( P3h2 ) gene, which hydroxylates 3′-prolines of the collagen IV alpha chains (Gly-3Hyp-4Hyp-Gly). Conditional podocyte knockout animals lacking gene expression expressed a collagen IV glomerulopathy, which included thin basement membranes and abnormalities reminiscent of AS [ 57 ]. This publication demonstrated that the prolyl-hydroxylation is not of decorative nature but of essential functional significance [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Nikolaou

Deltas

2022

Genes

View full text Add to dashboard Cite

Alport syndrome is a hereditary kidney disease caused by mutations in the three genes encoding for collagen IV: COL4A3, COL4A4, and COL4A5. Several mouse models have been created for the study of this disease with variable phenotypic outcomes. This review is an up-to-date presentation of the current mouse models existing in the literature with a detailed comparison of the phenotypic features characterizing each model. Although in humans it is primarily a glomerulopathy, data suggest that in some mouse models, the initial symptoms appear in the tubule-interstitial region rather than the glomerulus. Additionally, in some other models, the severity of disease in the tubule-interstitial region is affected by the genetic background. In conclusion, the phenotypic spectrum of each model appears to be affected by the model’s genetic background, the position of the genetic alteration within the gene, and the type of the genetic alteration. Despite these disparities, mouse models recapitulate with relatively high fidelity several features of the human disease, which makes them useful for studies aimed at better understanding cellular pathomechanisms and for finding new treatments.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Nikolaou

Deltas

2022

Genes

View full text Add to dashboard Cite

show abstract

“…At the ultrastructural level, one female patient showed TBMN and GBM irregularities reminiscent of AS. A conditional podocyte knockout mouse lacking the P3h2 gene also exhibited AS-like features [ 19 ]. This discovery maintains AS as a collagen IV protein nephropathy [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several authors diagnose these patients with autosomal dominant AS [ 14 , 15 ], although they rarely develop extrarenal symptoms or ultrastructural features pathognomonic of AS [ 16 , 17 , 18 ]. In a recent publication, a very rare form of TBMN and Alport-like nephropathy, caused by recessive mutations in the P3H2 gene which encodes the prolyl-3 hydroxylase gene, was reported [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece

Hadjipanagi

Papagregoriou

Koutsofti

et al. 2022

Genes

View full text Add to dashboard Cite

Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

show abstract

“…In this context, it appears also interesting that recently P3H2 Q12 , a podocyte-expressed collagen IV modifier, was identified as a potential novel drug target. 32…”

Section: Understanding Basement Membranesmentioning

confidence: 99%

Integrating basic science with translational research: the 13th International Podocyte Conference 2021

Lausecker

Koehler

Fresquet

et al. 2022

Kidney International

Self Cite

View full text Add to dashboard Cite

Loss of the collagen IV modifier prolyl 3-hydroxylase 2 causes thin basement membrane nephropathy

Cited by 17 publications

References 27 publications

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Novel and Founder Pathogenic Variants in X-Linked Alport Syndrome Families in Greece

Integrating basic science with translational research: the 13th International Podocyte Conference 2021

Contact Info

Product

Resources

About