Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

Papazachariou L ，Papagregoriou G ，Hadjipanagi D ，Demosthenous P ，Voskarides K ，Koutsofti C ，Stylianou K ，Ioannou P ，Xydakis D ，Tzanakis I ，Papadaki A ，Kallivretakis N ，Nikolakakis N ，Perysinaki G ，Gale DP ，Diamantopoulos A ，Goudas P ，Goumenos D ，Soloukides A ，Boletis I ，Melexopoulou C ，Georgaki E ，Frysira E ，Komianou F ，Grekas D ，Paliouras C ，Alivanis P ，Vergoulas G ，Pierides A ，Daphnis E ，Deltas C ... -  《-》

Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing.

Papazachariou L ，Demosthenous P ，Pieri M ，Papagregoriou G ，Savva I ，Stavrou C ，Zavros M ，Athanasiou Y ，Ioannou K ，Patsias C ，Panagides A ，Potamitis C ，Demetriou K ，Prikis M ，Hadjigavriel M ，Kkolou M ，Loukaidou P ，Pastelli A ，Michael A ，Lazarou A ，Arsali M ，Damianou L ，Goutziamani I ，Soloukides A ，Yioukas L ，Elia A ，Zouvani I ，Polycarpou P ，Pierides A ，Voskarides K ，Deltas C ... -  《PLoS One》

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 dis

Pierides A ，Voskarides K ，Athanasiou Y ，Ioannou K ，Damianou L ，Arsali M ，Zavros M ，Pierides M ，Vargemezis V ，Patsias C ，Zouvani I ，Elia A ，Kyriacou K ，Deltas C ... -  《-》

Autosomal dominant form of type IV collagen nephropathy exists among patients with hereditary nephritis difficult to diagnose clinicopathologically.

Type IV collagen nephropathies include Alport Syndrome and thin basement membrane nephropathy (TBMN), which are caused by mutations in COL4A3/A4/A5 genes. Recently, reports of patients with heterozygous mutations in COL4A3/A4 have been increasing. The clinical course of these patients has a wide variety, and they are diagnosed as TBMN, autosomal dominant Alport syndrome (ADAS), or familial focal segmental glomerular sclerosis. However, diagnosis, frequency and clinicopathological manifestation of them remains unclear. We tested COL4A3/A4/A5 genes in patients with hereditary nephritis that was difficult to diagnose clinicopathologically, and investigated who should undergo such testing. We performed immunostaining for α5 chain of type IV collagen [α5 (IV)] in 27 patients from 21 families who fitted the following criteria: (i) haematuria and proteinuria (± renal dysfunction); (ii) family history of haematuria, proteinuria, and/or renal dysfunction (autosomal dominant inheritance); (iii) no specific glomerulonephritis; and (iv) thinning, splitting, or lamellation of the glomerular basement membrane (GBM) on electron microscopy. Then we performed genetic testing in 19 patients from 16 families who showed normal α5 (IV) patterns. We conducted a retrospective analysis of their clinicopathological findings. Among 16 families, 69% were detected heterozygous mutations in COL4A3/A4, suggesting the diagnosis of TBMN/ADAS. Twenty-one percent of patients developed end stage renal disease. All patients showed thinning of GBM, which was accompanied by splitting or lamellation in seven patients. A considerable fraction of patients with hereditary nephritis that is difficult to diagnose clinicopathologically have TBMN/ADAS. It is important to recognize TBMN/ADAS and perform genetic testing in appropriate patients.

Imafuku A ，Nozu K ，Sawa N ，Hasegawa E ，Hiramatsu R ，Kawada M ，Hoshino J ，Tanaka K ，Ishii Y ，Takaichi K ，Fujii T ，Ohashi K ，Iijima K ，Ubara Y ... -  《-》

COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.

Voskarides K ，Damianou L ，Neocleous V ，Zouvani I ，Christodoulidou S ，Hadjiconstantinou V ，Ioannou K ，Athanasiou Y ，Patsias C ，Alexopoulos E ，Pierides A ，Kyriacou K ，Deltas C ... -  《-》