The 2014 International Workshop on Alport Syndrome

Alport syndrome, historically referred to as hereditary glomerulonephritis with sensorineural deafness and anterior lenticonus, is a genetic disease of collagen α3α4α5(IV) resulting in renal failure. The collagen α3α4α5(IV) heterotrimer forms a network that is a major component of the kidney glomerular basement membrane (GBM) and basement membranes in the cochlea and eye. Alport syndrome, estimated to affect 1 in 5000–10,000 individuals, is caused by mutations in any one of the three genes that encode the α chain components of the collagen α3α4α5(IV) heterotrimer: COL4A3, COL4A4, and COL4A5. Although angiotensin-converting enzyme inhibition is effective in Alport syndrome patients for slowing progression to end-stage renal disease, it is neither a cure nor an adequate long-term protector. The 2014 International Workshop on Alport Syndrome, held in Oxford, UK, from January 3–5, was organized by individuals and families living with Alport syndrome, in concert with international experts in the clinical, genetic, and basic science aspects of the disease. Stakeholders from diverse communities—patient families, physicians, geneticists, researchers, Pharma, and funding organizations—were brought together so that they could meet and learn from each other and establish strategies and collaborations for the future, with the overall aim of discovering much needed new treatments to prolong kidney function. Alport syndrome, historically referred to as hereditary glomerulonephritis with sensorineural deafness and anterior lenticonus, is a genetic disease of collagen α3α4α5(IV) resulting in renal failure. The collagen α3α4α5(IV) heterotrimer forms a network that is a major component of the kidney glomerular basement membrane (GBM) and basement membranes in the cochlea and eye. Alport syndrome, estimated to affect 1 in 5000–10,000 individuals, is caused by mutations in any one of the three genes that encode the α chain components of the collagen α3α4α5(IV) heterotrimer: COL4A3, COL4A4, and COL4A5. Although angiotensin-converting enzyme inhibition is effective in Alport syndrome patients for slowing progression to end-stage renal disease, it is neither a cure nor an adequate long-term protector. The 2014 International Workshop on Alport Syndrome, held in Oxford, UK, from January 3–5, was organized by individuals and families living with Alport syndrome, in concert with international experts in the clinical, genetic, and basic science aspects of the disease. Stakeholders from diverse communities—patient families, physicians, geneticists, researchers, Pharma, and funding organizations—were brought together so that they could meet and learn from each other and establish strategies and collaborations for the future, with the overall aim of discovering much needed new treatments to prolong kidney function. Alport syndrome is a hereditary glomerular disease leading almost inevitably to end-stage renal disease. The syndrome is usually associated with sensorineural hearing loss and distinct ocular abnormalities.1.Kashtan C.E. Familial hematuria.Pediatr Nephrol. 2009; 24: 1951-1958Crossref PubMed Scopus (47) Google Scholar In the early 1990s Alport syndrome was shown to be caused by defects in collagen α3α4α5(IV), one of the three network-forming isoforms of type IV collagen.2.Hudson B.G. Tryggvason K. Sundaramoorthy M. et al.Alport's syndrome, Goodpasture's syndrome, and type IV collagen.N Engl J Med. 2003; 348: 2543-2556Crossref PubMed Scopus (752) Google Scholar This isoform is the major collagen IV component of the kidney glomerular basement membrane (GBM).3.Hudson B.G. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family.J Am Soc Nephrol. 2004; 15: 2514-2527Crossref PubMed Scopus (143) Google Scholar Although there have been recent improvements in patient management, there is no cure for Alport syndrome. The 2014 International Workshop on Alport Syndrome, ‘Shining a Light on Alport Syndrome’, was held at the Said Business School in Oxford, UK, from January 3–5. This meeting was organized through the concerted efforts of patient advocacy groups from around the world. It brought together an internationally diverse group of physicians, geneticists, and scientists from academia and Pharma, many of whom were not specifically Alport syndrome experts, to learn about and discuss the latest findings regarding diagnosis, treatment, and molecular mechanisms of disease progression. The Workshop had four major areas of focus: Genetics/Diagnosis, Basic Science, Treatment, and Patient Registries/Clinical Trials. An important aspect of the Workshop was the ability of scientists working in laboratories to meet individuals and families affected by Alport syndrome and to hear firsthand their perspective about what it is like to live with the disease. Although most of the attendees typically focused on the kidney disease features of Alport syndrome, eye and hearing defects were also discussed as being very important diagnostic and quality-of-life aspects that need to be considered. As reported in the Genetics/Diagnosis session and at a special pre-meeting focused on the same topics, mutation screening of the relevant COL4 genes is now widely available.4.Hertz J.M. Thomassen M. Storey H. et al.Clinical utility gene card for: Alport syndrome.Eur J Hum Genet. 2012https://doi.org/10.1038/ejhg.2011.237Crossref Scopus (39) Google Scholar Because of this, although relatively expensive, increasing numbers of affected individuals have had their mutation(s) identified. There are currently six databases for variants in COL4A5, the gene affected in the X-linked, most common form of Alport syndrome. The consortium of genetic-testing laboratories for Alport syndrome has chosen to use the Leiden Open Variant Database system.5.Savige J. Ars E. Cotton R.G. et al.DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome.Pediatr Nephrol. 2013; 29: 971-977Crossref PubMed Scopus (17) Google Scholar This freely accessible database (http://www.lovd.nl/3.0/home) includes clinical features, multiple examples of the same variant from unrelated individuals, and normal variants. The value of internationally accessible, regularly updated variant databases is clear. Recently, members of the Alport Variant Consortium added 500 variants to the COL4A5 database, bringing the total number to 1900, with 1100 unique changes. The variants include 40% missense mutations and approximately 50% nonsense mutations. Glycine substitutions occur four times as often as substitutions of other amino acids in the Gly-X-Y triplet repeat collagenous segments. This is consistent with the necessity of a Gly at every third residue to form and stabilize the triple helical structure of the collagenous domain. As summarized by Frances Flinter, there are several molecular approaches for identifying variants. Although Sanger sequencing is the gold standard, custom next-generation sequencing panels, described by Michael Yau (GSTS Pathology, Guy’s & St Thomas’ Hospital, London, UK), plus whole-exome and whole-genome sequencing, are rapidly being validated and introduced into clinical practice. The challenges associated with the interpretation of variants were explained by Helen Storey (GSTS Pathology), as many mutations are novel and specific to individual families.6.Storey H. Savige J. Sivakumar V. et al.COL4A3/COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome.J Amer Soc Nephrol. 2013; 24: 1945-1954Crossref PubMed Scopus (92) Google Scholar There are clearly founder mutations in some populations, however—e.g. in Britain, and in Cyprus, where Constantinos Deltas (University of Cyprus, Nicosia, Cyprus) has been studying a large number of families in which significant renal impairment has been noted in association with a single autosomal COL4 mutation in some families.7.Pierides A. Voskarides K. Athanasiou Y. et al.Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2009; 24: 2721-2729Crossref PubMed Scopus (100) Google Scholar Mutation detection within COL4 genes remains incomplete partly because of missed rearrangements and cryptic splice site mutations. In some cases, RNA analysis is necessary in order to establish the potential pathogenicity of a variant. The tantalizing prospect of extracting RNA from podocytes in urine needs further exploration, as excreted podocytes could be a readily available source of RNA. The unexpected clinical variation among affected individuals in some families was discussed by Daniel Gale and Jie Ding and could reflect variable control of hypertension and other environmental influences; variable inheritance of mutations or copy number variants in modifier genes could also be important. The introduction of more comprehensive screening technologies such as next-generation sequencing and exome sequencing allows simultaneous screens for mutations in other potentially relevant genes. Moin Saleem (University of Bristol, Bristol, UK) presented a gene panel for proteinuria potentially containing up to 37 genes for Alport syndrome and focal segmental glomerulosclerosis, including NPHS1, NPHS2, MYH9, and complement pathway genes. It was noted that a clear genotype–phenotype correlation has emerged for X-linked Alport syndrome.8.Jais J.P. Knebelmann B. Giatras I. et al.X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study.J Amer Soc Nephrol. 2003; 14: 2603-2610Crossref PubMed Scopus (314) Google Scholar,9.Jais J.P. Knebelmann B. Giatras I. et al.X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.J Amer Soc Nephrol. 2000; 11: 649-657PubMed Google Scholar Large deletions and rearrangements, nonsense mutations, and missense mutations toward the carboxy terminus all result in more severe disease. In addition, some amino-acid substitutions (Arg, Glu, Asp) for Gly in the Gly-X-Y repeat collagenous regions are more damaging. Clifford Kashtan described the natural history and considerable variations in the presentation of Alport syndrome. Indeed, a lively debate is underway regarding the autosomal genes and the appropriate nomenclature for individuals with a heterozygous COL4A3 or COL4A4 mutation. Some such individuals have hematuria and may develop renal impairment later in life vs. patients with classic Alport syndrome, but they do not manifest any extrarenal features. Some experts regard them as carriers of autosomal recessive Alport syndrome, acknowledging that this genetic status is associated with thin basement membrane nephropathy and an increased risk of hypertension and renal impairment, whereas others describe them as having autosomal dominant Alport syndrome, although many of these patients do not fulfill the standard clinical diagnostic criteria.10.Savige J. Gregory M. Gross O. et al.Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.J Amer Soc Nephrol. 2013; 24: 364-375Crossref PubMed Scopus (253) Google Scholar Why is this issue so important? It is highly likely that the current EARLY PRO-TECT Alport trial of early ACE inhibition (www.clinicaltrials.gov; identifier NCT01485978) will be followed by other trials, as candidate therapies emerge from basic science research or from other clinical trials. It is thus essential that all patients who enroll in these trials have their diagnosis confirmed at the DNA level so that any possible genetic factors that may influence response to therapy are identified. Judith Savige noted that another diagnostic test that may be useful when genetic testing is not available is a retinal photograph that can show the characteristic fleck retinopathy or an optical coherence tomography scan that often shows temporal retinal thinning. It was also noted that the lens capsule removed during the surgery for lenticonus can be a good source of abnormal collagen α3α4α5(IV) for research, although this would depend upon the nature of the mutation. The Basic Science aspects of the workshop focused initially on collagen IV structure, biochemistry, and assembly of heterotrimeric collagen IV building blocks into networks. Billy Hudson (Vanderbilt University Medical Center, Nashville, Tennessee, USA) spoke about the involvement of the enzyme peroxidasin in catalyzing the formation of the novel sulfilimine bond.11.Bhave G. Cummings C.F. Vanacore R.M. et al.Peroxidasin forms sulfilimine chemical bonds using hypohalous acids in tissue genesis.Nat Chem Biol. 2012; 8: 784-790Crossref PubMed Scopus (173) Google Scholar,12.Vanacore R. Ham A.J. Voehler M. et al.A sulfilimine bond identified in collagen IV.Science. 2009; 325: 1230-1234Crossref PubMed Scopus (155) Google Scholar This bond, which was explained as important for strengthening the collagen IV network, links α chains in one heterotrimer to those in an adjacent heterotrimer via conserved Met and Lys residues. A phylogenetic investigation of this finding revealed that the sulfilimine bond is an ancient evolutionary adaptation first apparent in a subset of Cnidarians that was accompanied by the appearance of the peroxidasin gene.13.Fidler A.L. Vanacore R.M. Chetyrkin S.V. et al.A unique covalent bond in basement membrane is a primordial innovation for tissue evolution.Proc Natl Acad Sci USA. 2014; 111: 331-336Crossref PubMed Scopus (91) Google Scholar Peroxidasin’s enzymatic function was shown to involve the production of a bleach-like chemical that could theoretically be detrimental to the basement membrane this is one potential novel that could the that in Alport syndrome. important aspects of normal and Alport were (University of UK) described a analysis of total glomerular that revealed the of many to be in R. A. et analysis the of the glomerular Amer Soc Nephrol. 2014; 14: Scopus Google Scholar Some of these will be to the and could be in Alport to is type which is to be important in but could in the to collagen IV assembly or function. In collagen has been shown to be increased in Alport C.E. Y. of the and chains of collagen IV and of and in Alport PubMed Scopus Google Scholar presented of Alport a This a that of an abnormal Alport containing the collagen network to one also containing the collagen α3α4α5(IV) network is G. et of glomerular basement membrane defects in Alport syndrome.J Amer Soc Nephrol. 2014; PubMed Scopus Google Scholar of the collagen IV network at as late as was shown to kidney disease progression and the life It was reported the the with the the life As presented by Hospital, the of in the Alport by that the M. et of glomerular in Alport J 2013; PubMed Scopus Google Scholar of focal in which detrimental changes. This focal as a potential for slowing Alport syndrome. The involvement of and the of hypertension that increased et gene to Alport glomerular 2009; PubMed Scopus Google Scholar to the is a major in by the basic science group to be important for the the for to and from Alport patients to a of in the to the which to be to disease progression. There were major discussed for new The first was the in the Although most that gene gene or therapies be effective early during the of disease the of early the are as in and O. et therapy for Alport syndrome: the the Dial Transplant. 2009; 24: PubMed Scopus Google Scholar gene with O. et gene into kidney using an and in kidney first gene therapy of Alport Google Scholar as by Tryggvason and in a Alport The discussed at of the and that result from the in the of focal was by as a therapy to as was inhibition of collagen and the of which Alport disease progression in O. R. B. et of renal in hereditary type IV collagen Biol. 29: PubMed Scopus Google J. M. et and 1 of the glomerular basement membrane and loss of kidney in COL4A3 Biol. 2014; PubMed Scopus Google Scholar as reported by the group of on the of on of Alport have with some and others no An on the and therapies of Alport syndrome.Pediatr Nephrol. 2013; PubMed Scopus Google Scholar It was that efforts at slowing disease progression on the glomerular and the with of podocytes as a There was during the Workshop of findings in that the same mutation can result in highly variable of progression to kidney the that genetic has a significant et influence renal disease progression in a of Alport J PubMed Scopus Google R. et a to the molecular of Alport PubMed Scopus Google Scholar As next-generation sequencing could be in identifying the modifier genes and of into Alport was reported by (University of USA) to and but any on A. et of progression of renal Amer Soc Nephrol. 2012; PubMed Scopus Google Scholar The of the was also discussed by Gross as a very new to O. Deltas Alport syndrome from to the potential of current and the of Dial Transplant. Scopus (39) Google Scholar Although most of the attendees were focused on the of Alport syndrome also be for the testing of new their and life with the of new to Alport syndrome was identified as a This is because most are autosomal or gene whereas most patients have missense mutations in the X-linked COL4A5 and many of these mutations are Gly substitutions that likely network or all three the technologies for the as presented by UK), of a was to be a for the new were presented at the by Constantinos Deltas (University of Cyprus, Nicosia, has a Gly in COL4A3 that is to a mutation common in M. A. et for of the response in collagen IV Amer Soc Nephrol. 2014; PubMed Scopus Google Scholar and at The has a splice site mutation in that in and production of α3α4α5(IV) R. 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