Gelsolin amyloidosis associated with the p.D214N gelsolin gene mutation in a Chinese family

Shuang Wang; Dan-yang Li; Jin Xu; Wen-jing Song; Su-xia Wang

doi:10.23876/j.krcp.24.130

Amyloid gelsolin (AGel) amyloidosis is an autosomal dominant hereditary disease associated with mutation in the gelsolin (GSN) gene, AGel amyloidosis predominantly involves the cornea, peripheral and cranial nerves, it can also involve skin, heart, and kidney. Renal involvement in AGel amyloidosis is rare and has been reported in a few studies [1-8]. Here we report a family with gelsolin amyloidosis due to c.640G>A (p.D214N) mutation in the GSN gene.

This study was approved by the Ethics Committee of Peking University First Hospital (No. 2022-448). Informed consent was obtained from all the subjects.

A 45-year-old Chinese male presented with proteinuria for 8 months. His physical examinations were unremarkable. Urinalysis revealed moderate proteinuria of 2.33 g/24 hr. His serum albumin was 37.1 g/L and serum creatinine was 0.83 mg/dL. Serum immunoglobulins and serum-free light chains were normal. Serum and urine immunofixation electrophoresis were negative for monoclonal immunoglobulins. Bone marrow biopsy showed no evidence of a plasma cell disorder. A kidney biopsy was performed to investigate the cause of proteinuria.

Renal biopsy demonstrated massive amyloid deposits in glomeruli and focal amyloid deposits in tubulointerstitium, which displayed apple-green birefringence under polarized light (Fig. 1A, B). Electron microscopy revealed fibrillary deposits in the mesangium, manifested as unbranched fibrils measured 10 nm in thickness (Fig. 1D). By immunohistochemical staining, the amyloid deposits were positive for gelsolin protein (Fig. 1C).

The amyloid deposits were further typed by laser microdissection combing mass spectrometry (LMD-MS). Gelsolin was the most abundant amyloidogenic protein; 20 total spectra were identified and 27.75% coverage of protein sequence (Fig. 1G, H). Apolipoprotein E, serum amyloid P component, and apolipoprotein A-IV, which are amyloid signature proteins, were detected and consistent with the diagnosis of amyloidosis. Peripheral blood samples were collected, and the proband and three asymptomatic family members were screened for mutations of the GSN gene (Fig. 1E). Genetic analysis of the patient, his father, and his son revealed a mutation c.640G>A with heterozygous form (Fig. 1F), which results in a missense mutation of aspartic acid to asparagine at codon 214 (p.D214N). Further ophthalmologic examination including slit-lamp microscopy and confocal microscopy showed he had corneal lattice dystrophy. Clinical evaluation of his father and son showed no evidence of renal and cornea involvement.

Our patient was diagnosed with hereditary gelsolin amyloidosis, associated with a p.D214N mutation in the GSN gene. The patient was seen after 1 year, urinalysis reported mild proteinuria. Serum albumin was 44.8 g/L and serum creatinine was 1.0 mg/dL.

Gelsolin amyloidosis, also known as familial amyloidosis of the Finnish type, was first described in 1969 [2]. Subsequent studies showed it was caused by the mutations in the coding sequence of gelsolin, resulting in the aberrant folding process of secreted gelsolin and eventually leading to the formation of amyloid fibrils. To date, four amyloidogenic mutations in the GSN gene have been identified in renal AGel amyloidosis and their clinicopathological features are summarized in Table 1. It seemed that c.640G>A (p.D214N) was a more common mutation of AGel amyloidosis among the reported ones. Meanwhile, patients with this mutation tended to have extrarenal manifestations such as cranial neuropathy and corneal lattice dystrophy, while other mutations appeared to be renal-limited forms [5,7]. A study of family AGel amyloidosis showed an early onset, rapidly progressive renal disease with the homozygous form of c.640G>A (p.D214N) [3]. In contrast, the heterozygous cases reported in Japan [6], as well as in our case, presented with mild to moderate proteinuria and progressed slowly.

The amyloid deposition pattern in renal AGel amyloidosis is distinctive, with amyloid deposits mostly involved, and even limited to glomeruli. In our case, a kidney biopsy showed massive amyloid deposits in the glomeruli with focal amyloid deposits in the interstitium, no vascular amyloid deposits were found.

Subtyping of amyloid by MS has been proven to be sensitive and specific in clinical practice, especially for rare amyloid types. In this case, laboratory testing and immunofluorescence studies were all negative for monoclonal immunoglobulins and light chains. Then LMD-MS was performed, and MS analysis showed the amyloid signature proteins and the presence of amyloidogenic protein gelsolin. Further genetic analysis identified a p.D214N mutation in the GSN gene, and AGel amyloidosis involving the kidney and cornea was diagnosed finally.

In summary, we report the first case of renal AGel amyloidosis with p.D214N mutation in a Chinese family. Compared to other GSN gene mutations in renal AGel amyloidosis, the p.D214N mutation is more common and tends to have extrarenal involvement. LMD-MS analysis is valuable for subtyping amyloidosis, gene sequencing of amyloidogenic proteins can identify the underlying gene mutations and help to determine the further therapeutic strategy and prognosis.

Notes

Conflicts of interest

All authors have no conflicts of interest to declare.

Funding

This work was supported by the National Natural Science Foundation of China (grant No. 82170724).

Data sharing statement

The data presented in this study are available from the corresponding author upon reasonable request from the corresponding author.

Authors’ contributions

Conceptualization: SW, SxW

Data curation: SW

Methodology: SW, DL, JX, WS

Funding acquisition: SxW

Writing original draft: SW

Writing – review & editing: SxW

All authors read and approved the final manuscript.

Figure 1.

Kidney biopsy findings, family pedigree, genetic analysis, and amyloid typing of the proband.

(A, B) Congo red-positive deposits were found in glomeruli and focal tubulointerstitium, which displayed apple-green birefringence under polarized light (×200). (D) Electron microscopy showed amyloid fibrils, which displayed a swirling pattern in the central area. (C) Amyloid deposits in glomeruli were positive for gelsolin by immunohistochemical staining (×400). (E) Family pedigree, members with the GSN gene c.640G>A mutation by black symbols, unaffected members by white symbols, members not tested with grey symbols. (F) DNA sequencing of GSN gene, confirming the c.640G>A variant in the proband, his father and his son. Red arrow indicates the mutated site. (G, H) Mass spectrometry-based amyloid typing confirmed gelsolin as the amyloid protein, the covered peptides were highlighted in yellow.

Table 1.

Gene mutations and clinicopathological features of renal gelsolin amyloidosis

Study	Year	Age (yr)/sex	Base change	Amino acid change	Renal initial presentation	Extrarenal manifestations	Renal amyloid involvement
Meretoja [2]	1969	NA	c.640G>A	p.Asp214Asn	NA	Cutis laxa, cranial neuropathy, heart arrhythmia	NA
Maury et al. [3]	1992	39/Female	c.640G>A^a	p.Asp214Asn	Nephrotic syndrome	Corneal lattice dystrophy, cranial neuropathy, cardiac abnormalities	Glomeruli
Maury et al. [3]	1992	35/Female	c.640G>A^a	p.Asp214Asn	Nephrotic syndrome	Cutis laxa, corneal lattice dystrophy	Glomeruli
Ardalan et al. [4]	2007	25/Female	c.640G>A^a	p.Asp214Asn	Nephrotic syndrome	Cutis laxa, corneal lattice dystrophy, cranial neuropathy, retinitis pigmentosa	Glomeruli
Sethi et al. [5]	2013	75/Female	c.580G>A	p.Gly194Arg	Chronic kidney disease	Hypertension, rheumatoid arthritis, gout	Glomeruli
Yamanaka et al. [6]	2013	42/Female	c.640G>A^b	p.Asp214Asn	Proteinuria (0.89 g/day)	Hypertension, corneal lattice dystrophy	Glomeruli, interstitium, vessels
Yamanaka et al. [6]	2013	62/Female	c.640G>A^b	p.Asp214Asn	Proteinuria (1.7 g/day)	Cutis laxa, corneal lattice dystrophy, Diabetes mellitus, acromegaly, hypertension	Glomeruli, interstitium, vessels
Efebera et al. [7]	2014	62/Male	c.633C>A	p.Asn211Lys	Nephrotic range proteinuria	Lung cancer	Glomeruli
Zhang et al. [8]	2021	53/Male	c.520G>A	p.Asp174Asn	Proteinuria (1.45 g/day)	Cutis laxa, corneal lattice dystrophy, hypertension	Glomeruli, interstitium, vessels
Our case	2023	45/Male	c.640G>A^b	p.Asp214Asn	Proteinuria (2.33 g/day)	Corneal lattice dystrophy, hypertension	Golmeruli, interstitium

NA, not available.

^a Homozygous form and

^b heterozygous form.

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