COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome

Longo, Ilaria; Porcedda, Paola; Mari, Francesca; Giachino, Daniela; Meloni, Ilaria; Deplano, Carla; Brusco, Alfredo; Bosio, Maurizio; Massella, Laura; Lavoratti, Giancarlo; Roccatello, Dario; Frascà, Giovanni M.; Mazzucco, Gianna; Muda, Andrea Onetti; Conti, M I Bonanno; Fasciolo, F; Arrondel, Christelle; Heidet, Laurence; Renieri, Alessandra; Marchi, Mario

doi:10.1046/j.1523-1755.2002.00379.x

Cited by 198 publications

(149 citation statements)

References 32 publications

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“…However, it was not until 1990 that the genetic basis for what came to be known as X-linked Alport's syndrome was described (Barker et al, 1990;Hostikka et al, 1990;Myers et al, 1990;Pihlajaniemi et al, 1990). Since then, a large number of different mutations in the COL4A5 gene as well as in the COL4A3 and COL4A4 genes have been reported (Jais et al, 2000(Jais et al, , 2003Longo et al, 2002). These mutations not only include nonsense and missense mutations, but also mutations that affect splicing, stability of triple-helical structure, posttranslational modifications, and the assembly of chains into heterotrimeric molecules.…”

Section: Alport's Syndromementioning

confidence: 99%

Mammalian collagen IV

Khoshnoodi

Pedchenko

Hudson

2008

Microscopy Res & Technique

569

487

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Four decades have passed since the first discovery of collagen IV by Kefalides in 1966. Since then collagen IV has been investigated extensively by a large number of research laboratories around the world. Advances in molecular genetics have resulted in identification of six evolutionary related mammalian genes encoding six different polypeptide chains of collagen IV. The genes are differentially expressed during the embryonic development, providing different tissues with specific collagen IV networks each having unique biochemical properties. Newly translated α-chains interact and assemble in the endoplasmic reticulum in a chain-specific fashion and form unique heterotrimers. Unlike most collagens, type IV collagen is an exclusive member of the basement membranes and through a complex inter-and intramolecular interactions form supramolecular networks that influence cell adhesion, migration, and differentiation. Collagen IV is directly involved in a number of genetic and acquired disease such as Alport's and Goodpasture's syndromes. Recent discoveries have also highlighted a new and direct role for collagen IV in the development of rare genetic diseases such as cerebral hemorrhage and porencephaly in infants and hemorrhagic stroke in adults. Years of intensive investigations have resulted in a vast body of information about the structure, function, and biology of collagen IV. In this review article, we will summarize essential findings on the structural and functional relationships of different collagen IV chains and their roles in health and disease.

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Section: Alport's Syndromementioning

confidence: 99%

Mammalian collagen IV

Khoshnoodi

Pedchenko

Hudson

2008

Microscopy Res & Technique

569

487

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“…Although considerable advances have been made in our understanding of the molecular genetics and pathogenesis of these syndromes over the last decade, new genes and genetic loci continue to be identified for phenotypes that were once considered to be monogenic or oligogenic (2,4,9,16). In this report, we present a family with autosomal dominant progressive nephropathy with features of FSGS and AS including renal failure and deafness.…”

Section: Discussionmentioning

confidence: 98%

“…It has become evident that autosomal dominant nephropathy phenotype includes many disorders, such as FSGS and AS (2,4,6,7,15,16). Although considerable advances have been made in our understanding of the molecular genetics and pathogenesis of these syndromes over the last decade, new genes and genetic loci continue to be identified for phenotypes that were once considered to be monogenic or oligogenic (2,4,9,16).…”

Section: Discussionmentioning

confidence: 99%

“…AS also displays considerable phenotypic and genetic heterogeneity with the classic X-linked forms accounting for almost 85% of the cases, and the remaining 15% of cases showing autosomal inheritance (11)(12)(13)(14). X-linked AS (MIM 301050) is associated with type IV collagen alpha 5 chain (COL4A5) mutations, while mutations in alpha 3 chain (COL4A3) and alpha 4 chain (COL4A4) genes, located on chromosome 2q35-q37, have been found in cases of both autosomal recessive (MIM 203780) and dominant (MIM 104200) AS (12)(13)(14)(15)(16). Also, mutations in myosin heavy chain-9 nonmuscle gene (MYH9) cause Epstein and Fechtner syndromes, which can be associated with an autosomal dominant nephropathy that has some features of AS (17,18).…”

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confidence: 99%

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Autosomal Dominant Progressive Nephropathy with Deafness

Prakash¹,

Chung²,

Sinha³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are two major causes of end-stage renal disease (ESRD). A few families with autosomal dominant FSGS have been reported with linkage to chromosome 19q13 or 11q22, while AS is usually linked to mutations in type IV collagen (COL4) subunit genes. A phenotype resembling AS may also be seen with myosin heavy chain-9 (MYH9) gene mutations. This study ascertained a multigeneration family (CHP-177) with clinical aspects of both FSGS and AS where we identified a new locus for the trait. A genome-wide scan was performed with 400 markers, and fine mapping was performed for chromosome 11 markers. Data were analyzed by GENEHUNTER and VITESSE under various models. CHP-177 is a 39-member kindred residing near New Delhi, India, with seven affecteds and showed male-to-male transmission. Two members had ESRD. Renal biopsies showed both FSGS lesions and thin glomerular basement membranes. Five of the affecteds also had sensorineural deafness, which involved both low and high frequency in some members. The AS loci, i.e., COL4A3/COL4A4 and MYH9 (LOD scores: Ϫ6.1 and Ϫ4.3, respectively) and FSGS loci, on 19q13 and 11q22, were excluded from linkage. A significant evidence of linkage was observed for 11q24 region, with a multipoint LOD (z-score) of 3.2 for marker D11S4464 at ϭ 0. The z-1 confidence interval for the linked region spans a genetic distance of 7 cM. This study thus reports an autosomal dominant nephropathy with features of both FSGS and AS in which linkage to currently known loci for such phenotypes was excluded and a new locus on 11q24 was identified. The findings suggest further locus heterogeneity for the autosomal dominant nephropathy phenotype.

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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%