Pagniez Marie-Sophie, Fages Victor, Gatinois Clémence, Larrue Romain, Pottier Nicolas, Laboux Timothée, Lenain Rémi, Grunewald Olivier, Robert Thomas, Rigothier Claire, Mesnard Laurent, Glowacki François
Department of Nephrology, Kidney Transplantation and Dialysis, CHU Lille, University of Lille, Lille, France.
Department of Nephrology, Transplantation, Dialysis and Apheresis, CHU Bordeaux, Bordeaux, France.
Nephrol Dial Transplant. 2025 Aug 1;40(8):1522-1530. doi: 10.1093/ndt/gfaf011.
Unlike X-linked or autosomal recessive Alport syndrome, no clear genotype/phenotype correlation has yet been demonstrated in patients carrying a single variant of COL4A3 or COL4A4.
We carried out a multicentre retrospective study to assess the risk factors involved in renal survival in patients presenting a single pathogenic variant on COL4A3 or COL4A4.
A total of 97 patients presenting a single pathogenic variant of COL4A3 or COL4A4 were included. The prevalence of end-stage kidney disease (ESKD) during follow-up was 28.7% [median age 47.5 years (interquartile range 39.1-55.8). A total of 23 patients carried a 'severe' mutation (frameshift, stop gain, extensive deletion, impacting splicing) and 60 patients presented a glycine substitution in a collagenous domain. In patients with glycine missense variants, the location of the mutation in the distal exons was associated with worse renal survival with a more pronounced decline in the estimated glomerular filtration rate compared with variants in proximal exons. Conversely, the presence of a severe mutation did not impact renal survival.
Our results confirm that autosomal dominant Alport syndrome (ADAS) can lead to ESKD. We demonstrated that a glycine substitution involving the distal exons had a negative impact on renal survival in ADAS patients, probably due to a trimerization defect. This could help improve personalized follow-up in ADAS patients with glycine substitution and could be integrated into a future prognostic score to accurately predict renal outcomes.
与X连锁或常染色体隐性遗传性Alport综合征不同，携带COL4A3或COL4A4单一变异的患者尚未显示出明确的基因型/表型相关性。
我们开展了一项多中心回顾性研究，以评估携带COL4A3或COL4A4单一致病变异的患者肾脏存活的相关危险因素。
共纳入97例携带COL4A3或COL4A4单一致病变异的患者。随访期间终末期肾病（ESKD）的患病率为28.7%[中位年龄47.5岁（四分位间距39.1 - 55.8）]。共有23例患者携带“严重”突变（移码、终止密码子获得、广泛缺失、影响剪接），60例患者在胶原结构域出现甘氨酸替代。在甘氨酸错义变异患者中，与近端外显子变异相比，远端外显子突变的位置与肾脏存活率较低相关，估计肾小球滤过率下降更为明显。相反，严重突变的存在并不影响肾脏存活。
我们的结果证实常染色体显性遗传性Alport综合征（ADAS）可导致ESKD。我们证明涉及远端外显子的甘氨酸替代对ADAS患者的肾脏存活有负面影响，可能是由于三聚化缺陷。这有助于改善对有甘氨酸替代的ADAS患者的个性化随访，并可纳入未来的预后评分以准确预测肾脏结局。
