Novel gelsolin variant as the cause of nephrotic syndrome and renal amyloidosis in a large kindred

Abstract

Familial Amyloidosis of Finnish type (FAF) is a rare type of autosomal dominant hereditary amyloidosis associated with genetic variants of gelsolin. Three amyloidogenic mutations have previously been reported characteristically presenting with ophthalmologic abnormalities, progressive cranial neuropathy and cutis laxa. We report a novel gelsolin variant in a 62 year old man with nephrotic range proteinuria of 13.2 grams/day as the only presenting symptom. Renal biopsy followed by laser microdissection and mass spectrometry showed amyloidosis derived from gelsolin. DNA sequencing revealed the novel gelsolin mutation (c.633C>A) encoding p.N211K protein variant. Four of 13 asymptomatic family members were found to be heterozygous for the p.N211K mutation, three of whom had proteinuria of varying degree including one who proceeded to renal biopsy and was confirmed to have renal amyloidosis. Follow up of these cases might give us more insight into pathogenicity and potential treatment strategy of this atypical presentation of gelsolin amyloidosis.

The structure of N184K amyloidogenic variant of gelsolin highlights the role of the H-bond network for protein stability and aggregation properties

“…Among them, the D187N, D187Y, G167R and N184K substitutions are within the G2 domain ( Fig. 1, numbering of the mature plasma protein) (Meretoja 1969;de la Chapelle et al 1992;Sethi et al 2013;Efebera et al 2014). The D187N, D187Y substitutions impair Ca 2+ binding to G2, destabilize the G2 fold and increase its conformational flexibility ( Fig.…”

A Nanobody‐Based Approach to Amyloid Diseases, the Gelsolin Case Study

“…The fourth mutation, G167R, possibly has a destabilizing effect on hydrogen bonding as it is close to Q164. It should be noted that both the N184K and G167R mutations have only recently been discovered in two isolated patients and their kindred [2,3]. The overall majority of patients carry the D187N/Y mutation, but it is nevertheless noteworthy to observe that these pathological mutations are all in G2 of gelsolin, pointing to this region as a gelsolin stability sensor.…”

“…At the moment, there are four known mutations, which cause gelsolinrelated amyloidosis: D187N, D187Y, G167R and the recently discovered N184K [1][2][3].…”

“…Gelsolin amyloidosis is an autosomal-dominant inherited disease caused by a point mutation in the gelsolin gene; G640A and G640T are most common; G580A and C633A were more recently discovered [1][2][3]. At the protein level, these mutations result in the amino acid substitutions D187N, D187Y, G167R and N184K in gelsolin domain 2.…”

High-resolution crystal structure of gelsolin domain 2 in complex with the physiological calcium ion

“…Among the six gelsolin domains, G2 has been characterized the most [9][10][11][12][13][14][15][16], because four mutations in this domain (D187N, D187Y, G167R and N184K; according to the numbering of the mature plasma protein) have been described to be responsible for a rare genetic disease named AGel amyloidosis [17][18][19][20]. AGel amyloidosis is an autosomal-dominant monogenic disease.…”