Autosomal recessive Alport syndrome: an in-depth clinical and molecular analysis of five families

Longo, Ilaria; Scala, Elisa; Mari, Francesca; Caselli, Rossella; Pescucci, Chiara; Mencarelli, Maria Antonietta; Speciale, Caterina; Giani, Marisa; Bresin, Elena; Caringella, Domenica A.; Borochowitz, Zvi; Siriwardena, Komudi; Winship, Ingrid; Renieri, Alessandra; Meloni, Ilaria

doi:10.1093/ndt/gfi312

Cited by 44 publications

(34 citation statements)

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“…Until recently, the causes of familial hematuric nephropathies were restricted mostly to mutations in the type IV collagen genes, responsible for the X-linked or autosomal recessive Alport syndrome (3)(4)(5)(6). Heterozygous mutations in COL4A3/ COL4A4 genes are responsible for up to 40% of families with thin basement membrane disease (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Familial C3 Glomerulopathy Associated with CFHR5 Mutations

Athanasiou

Voskarides²,

Gale³

et al. 2011

Clinical Journal of the American Society of Nephrology

132

119

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Summary Background and objectivesComplement factor H and related proteins (CFHR) are key regulators of the alternative complement pathway, where loss of function mutations lead to a glomerulopathy with isolated mesangial C3 deposits without immunoglobulins. Gale et al. (12) reported on 26 patients with the first familial, hematuric glomerulopathy caused by a founder mutation in the CFHR5 gene in patients of Cypriot descent living in the United Kingdom. CFHR5 nephropathy is clinically characterized by continuous microscopic hematuria whereas some patients present with additional episodes of synpharyngitic macrohematuria, associated with infection and pyrexia. A subgroup of patients, particularly men, develop additional proteinuria, hypertension, and chronic renal disease or ESRD.Design, setting, participants, & measurements We herewith expand significantly on the study by Gale et al., reporting on histologic, molecular, and clinical findings in 91 patients from 16 families with the same founder mutation.Results Eighty-two patients (90%) exhibited microscopic hematuria; 51 (62%), exhibited only microscopic hematuria, whereas the remaining 31 additionally had proteinuria (38%); 28 proteinuric patients developed chronic renal failure (CRF). Among carriers of CFHR5 mutation aged Ͼ50 years, 80% of the men and 21% of the women developed CRF; 18 developed ESRD (14 men [78%], 4 women [22%]). ConclusionsThe diagnosis of CFHR5-related, isolated C3 glomerulopathy was established in 2009 using newly described mutation analysis after decades of follow-up with unclear diagnoses, occasionally confused with IgA nephropathy. This larger patient cohort establishes the clinical course, significant variable expressivity, and marked gender difference regarding the development of CRF and ESRD.

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Section: Introductionmentioning

confidence: 99%

Familial C3 Glomerulopathy Associated with CFHR5 Mutations

Athanasiou

Voskarides²,

Gale³

et al. 2011

Clinical Journal of the American Society of Nephrology

132

119

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“…Mutations in COL4A3 and COL4A4, encoding the a3(IV) and a4(IV) chains, are associated with autosomal AS. In the autosomal recessive form, patients frequently reach end stage renal failure (ESRF) before the end of the second decade, 7 and women are as severely affected as men. Heterozygous parents can present without any symptoms, with isolated microhematuria, which corresponds to what is observed in benign familial hematuria (BFH), or with a progressive renal disease, like in autosomal dominant AS.…”

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confidence: 99%

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Morinière¹,

Dahan

Hilbert

et al. 2014

Journal of the American Society of Nephrology

136

131

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Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the webbased sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.

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“…To date, 71 COL4A3 variants that include mis-sense, nonsense, deletion, insertion, and splice-site changes have been determined, 52 of which are related with autosomal-recessive or autosomaldominant AS. The other COL4A3 mutations have been found to be related with hematuria, focal segmental glomerulosclerosis, microhematuria, and proteinuria, and one mutation has been found to be related with chronic obstructive pulmonary disease Ding et al, 1995;Knebelmann et al, 1995;Van Der Loop et al, 2000;Heidet et al, 2001;Badenas et al, 2002;Longo et al, 2002;Tazon et al, 2003;Pescucci et al, 2004;Wang et al, 2004;Nagel et al, 2005;Longo et al, 2006;Hou et al, 2007;Slajpah et al, 2007;Voskarides et al, 2007;Hou et al, 2008;Kim et al, 2008, Hoefele et al, 2010Zhang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%