Alport Syndrome: Clinical Spectrum and Therapeutic Advances

Gregorio, Vanessa De; Caparali, Bilge; Shojaei, Azadeh; Ricardo, Samantha; Barua, Moumita

doi:10.1016/j.xkme.2023.100631

Cited by 10 publications

(13 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, recent studies are questioning this statistical claim and revealing a shift in our understanding. These results are based on advancements in molecular genetic testing for ATS, and studies that estimated the frequencies of COL4A3, COL4A4, and COL4A5 PVs in sequencing databases of populations but without known neither kidney disease nor adjusting for the disease penetrance of individual variants [19][20][21]. In our population, this difference in transmission patterns can be attributed to the high rate of consanguinity in Tunisian families [22].…”

Section: Discussionmentioning

confidence: 89%

Inversion of the Frequencies of Autosomal Recessive and X-Linked Dominant Forms of Alport Syndrome in the Tunisian Population

Mariem,

Achour,

Kraoua

et al. 2023

Preprint

View full text Add to dashboard Cite

Background: Alport syndrome is defined by the co-occurrence of hematuria, renal failure, and a family history of renal failure or hematuria. Pathogenic variants in COL4A3, COL4A4, and COL4A5 cause this phenotype. These genes code for the α3, α4, and α5 chains of collagen IV found in the kidneys, eyes, and cochlea. This explains the frequent association of extra-renal signs, such as bilateral sensorineural deafness and ocular abnormalities. Different modes of transmission have been reported. X-linked transmission is attributed to the pathogenic variants of COL4A5, while homozygous pathogenic variants of COL4A3 or COL4A4 lead to autosomal recessive inheritance. The digenic form occurs when a pathological variation in both COL4A3 and COL4A4coexist. Additionally, autosomal dominant inheritance can occur due to heterozygous pathogenic variants in COL4A3or COL4A4. In this study, we investigated 45 patients with Alport syndrome from 11 Tunisian families to establish their clinical and genetic characteristics. Methods: Clinical data were collected retrospectively, and molecular analysis of COL4A3, A4,andA5 was performed. Among the 45 patients, whole-exome sequencing was performed on 11 individuals, with one patient selected from each family. All candidate pathogenic variations were validated by Sanger sequencing. Cascade screening in the family of each proband allowed us to expand the number of individuals tested to 53 to verify the presence of the pathogenic variant found in their family. Results: We identified 9 likely pathogenic variations among 11 index cases. Six were novel variations and three were known ones. Of these, five out of nine were in the COL4A3 gene, while four out of nine were found in the COL4A5 gene. Frame-shift, nonsense, missense, and alternative splicing variants were detected in our cohort. Most of these variants affected the Gly-XY codon.Thirty out of the 45 clinically identified siblings were tested and confirmed for Alport syndrome. Cascade screening then identified 3 additional affected individuals, along with 10 unaffected siblings and 10 unaffected parents.The mode of inheritance of Alport syndrome was autosomal recessive in 6 familiesand X-linked in 4 families. Conclusions: This study represents the first Tunisian screening of the mutational spectrum of Alport syndrome. It contributes new pathogenic variants to the literature and demonstrates that autosomal recessive inheritance of Alport syndrome is more frequent in the Tunisian population than the X-linked dominant form as reported in the literature.

show abstract

Section: Discussionmentioning

confidence: 89%

Inversion of the Frequencies of Autosomal Recessive and X-Linked Dominant Forms of Alport Syndrome in the Tunisian Population

Mariem,

Achour,

Kraoua

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…For COL4a1/a2/a3 protein expression profiles exist (The Human Protein Atlas, 2023). A defect of the α-chains COL4a3/a4/a5 can lead to Alport syndrome which affects the basement membranes of the kidney, inner ear, and eye (Gregorio et al, 2023; Imafuku et al, 2018; Shulman et al, 2021; Deltas, 2022). Although part of the bigger subnetwork of FACITs, network-forming collagens and transmembrane collagens, there is a strong bond between COL8a1/a2 and COL10a1.…”

Section: Discussionmentioning

confidence: 99%

“…At a lower threshold of 17.0, a connection between COL4 and COL7 can be seen as mentioned in the literature (Roig-Rosello and Rousselle, 2020; Brittingham et al, 2006). A defect of the α-chains COL4a3/a4/a5 can lead to Alport syndrome which affects the basement membranes of the kidney, inner ear, and eye (Gregorio et al, 2023; Imafuku et al, 2018; Shulman et al, 2021; Deltas, 2022). The second cluster is formed by COL8a1, COL8a2 and COL10a2.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Constructing networks for comparison of collagen types

Wesp,

Scholz,

Ziermann-Canabarro

et al. 2023

Preprint

View full text Add to dashboard Cite

Collagens are structural proteins that are predominantly found in the extracellular matrix, where they are mainly responsible for the stability and structural integrity of various tissues. There are several different types of collagens, some of which differ significantly in form, function, and tissue specificity. Subdivisions into so-called collagen families exist, which are defined on the basis of mainly clinical research. Collagens contain polypeptide strands (ɑ-chains). Their sequences are often analysed in view of clinical aspects, but problems arise with highly homologous sequence segments. To increase the accuracy of collagen classification and prediction of their functions, the structure of these collagens and their expression in different tissues could result in a better focus on sequence segments of interest. Here, we analyse collagen families with different levels of conservation. As a result, families with strong interchain hydrogen bonds can be found, such as fibrillar collagens, network-forming collagens, and FACITs. Moreover, collagen IV α-chains form their own cluster, and other collagen α-chains do not bond at all.

show abstract

“… 11 , 12 Furthermore, previous studies have demonstrated that the inhibition of the renin–angiotensin system reduces proteinuria and decreases the rate of glomerulosclerosis and disease progression in patients with Alport syndrome. 13 , 14 Moreover, a cohort study of nephronophthisis suggested that the use of angiotensin-converting enzyme inhibitors was an independent risk factor associated with early-onset ESRD in patients with pathological variants of NPHP1 . 15 Therefore, accurately diagnosing inherited kidney diseases may delay CKD progression and avoid RRT.…”

mentioning

confidence: 99%

Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology

Fujimaru,

Mori,

Chiga

et al. 2024

Kidney International Reports

View full text Add to dashboard Cite

Alport Syndrome: Clinical Spectrum and Therapeutic Advances

Cited by 10 publications

References 123 publications

Inversion of the Frequencies of Autosomal Recessive and X-Linked Dominant Forms of Alport Syndrome in the Tunisian Population

Inversion of the Frequencies of Autosomal Recessive and X-Linked Dominant Forms of Alport Syndrome in the Tunisian Population

Constructing networks for comparison of collagen types

Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology

Contact Info

Product

Resources

About