Genotype–phenotype correlation in X‐linked Alport syndrome patients carrying missense mutations in the collagenous domain of <i>COL4A5</i>

Tsiakkis, D; Pieri, Myrtani; Koupepidou, Panayiota; Δημοσθένους, Παναγιώτα; Panayidou, Klea; Deltas, Constantinos

doi:10.1111/j.1399-0004.2012.01849.x

Cited by 21 publications

(9 citation statements)

References 6 publications

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“…The pathogenicity was considered to be “likely pathogenic” under the ACMG guidelines. Since the number of side chain carbon atoms was associated with the age of onset of ESKD in a patient with glycine substitution [ 26 ], regular follow-up will be necessary for Patient 5.…”

Section: Discussionmentioning

confidence: 99%

Mutation Analysis of Thin Basement Membrane Nephropathy

Hirabayashi

Katayama

Mori

et al. 2022

Genes

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Thin basement membrane nephropathy (TBMN) is characterized by the observation of microhematuria and a thin glomerular basement membrane on kidney biopsy specimens. Its main cause is heterozygous mutations of COL4A3 or COL4A4, which also cause late-onset focal segmental glomerulosclerosis (FSGS) or autosomal dominant Alport syndrome (ADAS). Thirteen TBMN cases were analyzed using Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and exome sequencing. Ten heterozygous variants were detected in COL4A3 or COL4A4 in nine patients via Sanger sequencing, three of which were novel variants. The diagnostic rate of “likely pathogenic” or “pathogenic” under the American College of Medical Genetics and Genomics guidelines was 53.8% (7 out of 13 patients). There were eight single nucleotide variants, seven of which were glycine substitutions in the collagenous domain, one of which was a splice-site single nucleotide variant, and two of which were deletion variants. One patient had digenic variants in COL4A3 and COL4A4. While MLPA analyses showed negative results, exome sequencing identified three heterozygous variants in causative genes of FSGS in four patients with no apparent variants on Sanger sequencing. Since patients with heterozygous mutations of COL4A3 or COL4A4 showed a wide spectrum of disease from TBMN to ADAS, careful follow-up will be necessary for these patients.

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Section: Discussionmentioning

confidence: 99%

Mutation Analysis of Thin Basement Membrane Nephropathy

Hirabayashi

Katayama

Mori

et al. 2022

Genes

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“…One study that only looked at triple helical glycine substitutions suggested that mutations in exons 1–20 (amino terminal) might have been less severe than those in exons 21–47 (carboxy terminal) 40 while a second, larger study found that mutations nearer the amino terminus were more severe 41 . Finally, a recent study suggested that missense substitutions for bulkier amino acids were associated with more severe outcomes 43 .…”

Section: ) Genotype–phenotype Correlations In Patients With Mutationmentioning

confidence: 99%

Genotype-phenotype correlations in pathology caused by collagen type IV alpha 1 and 2 mutations

Jeanne¹,

Gould²

2017

Matrix Biology

115

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COL4A1 and COL4A2 are extracellular matrix proteins that form heterotrimers and are present in nearly all basement membranes in every organ. In the past decade, COL4A1 and COL4A2 mutations have been identified to cause a multi-system disorder for which penetrance and severity of constituent phenotypes can greatly vary. Here, we compare the outcomes of more than 100 mutations identified in patients and data from a murine allelic series to explore the presence of genotype-phenotype correlations – many of which are shared among other types of collagen. We find that there is a frequency bias for COL4A1 over COL4A2 mutations and that glycine (Gly) substitutions within the triple helical domain are the most common class of mutations. Glycine is most often replaced by a charged amino acid, however the position of the mutation, and not the properties of the substituting amino acid, appear to have a greater influence on disease severity. Moreover, the impact of position is not straightforward. Observations from a murine allelic series suggest that mutations in the NC1 domain may result in relatively mild phenotypes via a ‘quantitative’ mechanism similar to other types of collagens, however, this effect was not apparent in human reports. Importantly, other position-dependent effects had differential impacts depending on the phenotype of interest. For example, the severity of cerebrovascular disease correlated with an amino-to-carboxy severity gradient for triple-helical glycine substitutions whereas the penetrance and severity of myopathy and nephropathy appear to involve a functional sub-domain(s). Greater understanding of genotype-phenotype correlations and the interaction of consequences of different mutations will be important for patient prognosis and care and for developing mechanism-based therapeutics to treat individual components of this emerging syndrome.

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“…Glisin, polipeptit zincirlerin birbirine bağlanması sırasında ortada yer alıriken, sıklıkla prolin ve hidroksiprolinden oluşan X ve Y uçları ısısal dayanıklılığı sağlamaktadır. 4,5 Farklı kollajen tiplerinden Tip 1, 2, 3 ve 5 fibriler yapı oluştururken, Tip 4 kollajen ekstraselüler matrikste bir protein ağı oluşturmaktadır. Tip 4 kollajen yapısındaki alfa zinciri altı farklı gen tarafın-dan kodlanır (α1 -α6).…”

Section: Ti̇p 4 Kollajenunclassified

“…tarafından yayımlan-mıştır. 19 Bu ailede G472R mutasyonu tanımlanan; ağır etkilenmiş bir erkek hasta ve orta derecede Turkiye Klinikleri J Pediatr 2016;25 (4) bulguları olan bir kadın hasta rapor edilmiştir. 2013 yılında akraba evliliği olan bir başka Türk ailede ise COL4A3 geninde yeni bir "missense" mutasyon (c2T>C; pM1T) tanımlanmıştır.…”

Section: Hafi̇f X'e Bağli Alport Sendromu Ve Hi̇pomorfi̇k Col4a5 "Missenunclassified