Six new cases of <scp>CRB2‐related</scp> syndrome and a review of clinical findings in 28 reported patients

Adutwum, Michelle; Hurst, Anna; Mirzaa, Ghayda; Kushner, Jessica D.; Rogers, Caleb; Khalek, Nahla; Cristancho, Ana G.; Burrill, Natalie; Seifert, Michael E.; Scarano, Maria I.; Schnur, Rhonda E.; Slavotinek, Anne

doi:10.1111/cge.14222

Cited by 6 publications

(3 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, 37 cases with CRB2 mutations have been described ( 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 ). Similar to CRB1 mutations, most of these mutations are located in the extracellular domain ( 65 ).…”

Section: Discussionmentioning

confidence: 99%

Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina

Stehle,

Imventarza,

Woerz

et al. 2024

Life Sci. Alliance

View full text Add to dashboard Cite

Crumbs homolog 1(CRB1) is one of the key genes linked to retinitis pigmentosa and Leber congenital amaurosis, which are characterized by a high clinical heterogeneity. The Crumbs family member CRB2 has a similar protein structure to CRB1, and in zebrafish, Crb2 has been shown to interact through the extracellular domain. Here, we show that CRB1 and CRB2 co-localize in the human retina and human iPSC-derived retinal organoids. In retina-specific pull-downs, CRB1 was enriched in CRB2 samples, supporting a CRB1–CRB2 interaction. Furthermore, novel interactors of the crumbs complex were identified, representing a retina-derived protein interaction network. Using co-immunoprecipitation, we further demonstrate that human canonical CRB1 interacts with CRB1 and CRB2, but not with CRB3, which lacks an extracellular domain. Next, we explored how missense mutations in the extracellular domain affect CRB1–CRB2 interactions. We observed no or a mild loss of CRB1–CRB2 interaction, when interrogating various CRB1 or CRB2 missense mutants in vitro. Taken together, our results show a stable interaction of human canonical CRB2 and CRB1 in the retina.

show abstract

Section: Discussionmentioning

confidence: 99%

Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina

Stehle,

Imventarza,

Woerz

et al. 2024

Life Sci. Alliance

View full text Add to dashboard Cite

show abstract

“…4 ) [ 10 ]. Recently, a phenotype-genotype correlation has been suggested in view of the clustering of pathogenic variations in exons 8 and 10 in patients presenting with kidney anomalies associated to hydrocephalus, whereas variations in exons 12 and 13 seems to be associated with isolated renal disease [ 17 ]. Our data are consistent with this hypothesis, indeed our patients also had variants in exons 8 and 10, but one of them had isolated hydrocephalus.…”

Section: Discussionmentioning

confidence: 99%

Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla

Tessier

Roux

Boutaud

et al. 2023

acta neuropathol commun

View full text Add to dashboard Cite

Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (β-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell–cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.

show abstract

“…In kidneys, it regulates differentiation and epithelialization of podocyte cells which are the main regulators for renal glomerulus filtration [1]. Until now, total thirty-two variations have been identified in the gene causing different types of kidney disorder [17][18][19] http://www.hgmd.cf.ac.uk/ac/all.php accessed on 26 June 2022). Here, we have identified the very first familial case of Pakistani origin of nephrotic syndrome caused by a novel homozygous splice site variant in the gene.…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Revealed a Novel Splice Site Variant in the CRB2 Gene Underlying Nephrotic Syndrome

Simaab

Krishin

Alaradi³

et al. 2022

Medicina

View full text Add to dashboard Cite

Background and Objectives: Nephrotic syndrome (NS) is a kidney disease where the patient has a classic triad of signs and symptoms including hypercholesterolemia, hypoalbuminemia, proteinuria (>3.5 g/24 h), and peripheral edema. In case of NS, the damaged nephrons (structural and functional unit of the kidney) filter unwanted blood contents to make urine. Thus, the urine contains unwanted proteins (proteinuria) and blood cells (hematuria), while the bloodstream lacks enough protein albumin (hypoalbuminemia). Nephrotic syndrome is divided into two types, primary NS, and secondary NS. Primary NS, also known as primary glomerulonephrosis, is the result of a glomerular disease that is limited to the kidney, while secondary NS is a condition that affects the kidney and other parts of the body. The main causes of primary NS are minimal change disease, membranous glomerulonephritis, and focal segmental glomerulosclerosis. In the present study we recruited a family segregating primary NS with the aim to identify the underlying genetic etiology. Such type of study is important in children because it allows counseling of other family members who may be at risk of developing NS, predicts risk of recurrent disease phenotypes after kidney transplant, and predicts response to immunosuppressive therapy. Materials and Methods: All affected individuals were clinically evaluated. Clinical examination, results of laboratory tests, and biopsy investigations led us to the diagnosis. The next-generation sequencing technique (whole-exome sequencing) followed by Sanger sequencing identified a novel homozygous splice site variant (NM_173689.7: c.941-3C>T) in the CRB2 gene. The variant was present in a homozygous state in the affected individuals, while in a heterozygous state in phenotypically normal parents. Results: The study expanded the spectrum of the mutations in the gene CRB2 responsible for causing NS. Conclusions: In addition, the study will also help in genetic counseling, carrier testing, and prenatal and/or postnatal early diagnosis of the disease in the affected family.

show abstract

Six new cases of CRB2‐related syndrome and a review of clinical findings in 28 reported patients

Cited by 6 publications

References 5 publications

Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina

Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina

Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla

Exome Sequencing Revealed a Novel Splice Site Variant in the CRB2 Gene Underlying Nephrotic Syndrome

Contact Info

Product

Resources

About