1 INSERM U25, Laboratoire d'Immunologie Clinique, Hôpital Necker, 161 rue de Sèvres, F-75015 Paris, 3 Laboratoire de Neuropharmacologie et Neurochimie, Université Claude Bernard, 8 Avenue Rockefeller, F-69373 Lyon, France, 4 NYU Medical Center, Department of Pathology, 550 First Avenue, New York, NY 10016, USA, 5 INSERM U489 and Renal Division, Hôpital Tenon, 4 rue de la Chine, F-75020 Paris, France, 6 Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439, USA
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Abstract |
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Keywords: BenceJones protein/human/kidney/myeloma/protein structure
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Introduction |
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Light chains may be of kappa or lambda type, and also they are often secreted as free subunits. Toxic effects of monoclonal Ig free LC towards kidney tubular cells may be an important factor of renal insufficiency in patients with myeloma, but their mechanism remains obscure. In the most common form of `myeloma kidney' disease, which affects about one third of patients (Ivanyi, 1990), obstruction by casts, due to precipitation of LCs with TammHorsfall protein in distal tubules, is a major factor of acute renal failure (Sanders, 1994
); myeloma cast nephropathy actually is a multifactorial complex disease, in which factors such as affinity of LC for TammHorsfall protein (Huang et al., 1993
; Huang and Sanders, 1995
) and LC resistance to proteases (Leboulleux et al., 1995
) are involved to variable degrees. On the other hand, tubular atrophy and degeneration related to LC toxicity also participate in the pathology in many cases (DeFronzo et al., 1978
; Leboulleux et al., 1995
). Deleterious effects of LCs, especially of type kappa, on proximal tubules were evidenced by several authors using experimental animal models (Clyne et al., 1974
; Sanders et al., 1987
, 1988
) and in vitro testing of tubular cell functions (Batuman et al., 1994
). However, myeloma patients may have prolonged LC proteinuria and normal renal function (Kyle et al., 1982
; Coward et al., 1985
; Solomon et al., 1991
). That nephrotoxicity is mainly determined by LC intrinsic factors was confirmed by the pathological correlations observed after intraperitoneal injections in mice (Solomon et al., 1991
). At one end of the spectrum of LC tubulopathies, patients are affected with a selective impairment of proximal tubule functions, the Fanconi's syndrome. Because it is a better defined entity, this condition is an interesting model for studying the mechanisms of LC tubular toxicity.
Fanconi's syndrome is characterized by biological and clinical features resulting from the impairment of kidney proximal tubule functions, especially reabsorption of a number of filtered substances (Lee et al., 1972). The most typical manifestations are a generalized aminoaciduria, glycosuria with normal glycemia, metabolic acidosis and increased clearances of uric acid and phosphate. Phosphate loss may be responsible for osteomalacia, with bone pain and pseudofractures (Lee et al., 1972
; Rao et al., 1987
; Clarke et al., 1995
). In adults, myeloma or other plasma cell dyscrasias secreting a free LCalmost always of kappa isotypeare a major cause of Fanconi's syndrome. According to previously reported studies (Maldonado et al., 1975
; Schillinger et al., 1993
), in virtually all cases the diagnosis of Fanconi's syndrome preceded that of the underlying hematological disorder, generally a `smoldering' myeloma. The slowly progressive character of the tumor is likely to be related to accumulation of crystals in the plasma cells (Engle and Wallis, 1957
; Costanza and Smoller, 1963
; Maldonado et al., 1975
). In these initial series, identical crystals were demonstrated in proximal tubule epithelial cells in all cases where they had been searched for. More recently, we showed that accumulation and crystallization in the lysosomes of tubular cells and endoplasmic reticulum of plasma cells were related to the resistance of the LC variable (V) domain to proteolysis by several enzymes (Aucouturier et al., 1993
). Resistance of the V domain to degradation by cathepsin B, a major lysosomal enzyme of proximal tubular cells, was a specific feature of all studied kappa LCs from patients with Fanconi's syndrome (Leboulleux et al., 1995
), and could explain their cellular toxicity. All studied kappa V domains from patients with intracellular crystals were found to have the most homology to a single germline V segment sequence, LCO2/O12 (Rocca et al., 1995
).
Interestingly, myeloma associated Fanconi's syndrome may also occur without evidence of intracellular crystallization, even when searched for by electron microscopy (Leboulleux et al., 1995); in one such case, the LC V domain likely derived from another germline V segment, LCO8/O18 (Rocca et al., 1995
). In the present study, we have analyzed the protein sequences of two other kappa LC V domains from patients with Fanconi's syndrome but no intracellular crystal, in order to look for distinctive structural features of this peculiar form of the disease. N-terminal sequences of LCs from two further patients with Fanconi's syndrome and intracellular crystals were also determined. Data were analyzed in comparison with three-dimensional models of our previously published patients (Aucouturier et al., 1993
; Rocca et al., 1995
).
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Material and methods |
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Main pathological and hematological data from eight patients with well-characterized Fanconi's syndrome are presented on Table I. Patients CHEB, TRE, TRO, HAL have been previously described (Leboulleux et al., 1995
), and detailed biological, morphological and clinical presentations of the others will be published elsewhere (T.Messiaen, personal communication). In two patients (HAL and VAL), associated cast nephropathy was evidenced by histological study of kidney biopsies. In patient LEC, some myeloma casts were evidenced but they were less numerous than in patients HAL and VAL. In all patients a specific impairment of proximal tubule reabsorption functions could be clearly demonstrated, based on generalized aminoaciduria, glycosuria with normal glycemia and increased clearances of uric acid and phosphate. It is worth noting that although all Fanconi's syndrome cases with kidney and plasma cell crystals were associated with a low mass tumor, two of the three patients in whom no crystal could be demonstrated had a more aggressive myeloma featuring severe osteolytic lesions. One patient (SAU) with a kappa LC myeloma without renal complication, as proved by renal biopsy, was studied as a control.
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All urinary proteins were precipitated with 50% saturated ammonium sulfate at 4°C. Samples from patients LEC, VAL and SCH were then fractionated by DEAE-Trisacryl (Sepracor, Villeneuve la Garenne, France) chromatography in 10 mM TrisHCl buffer pH 8 with a 0 to 0.3 M NaCl gradient. Fractions were tested by standard agarose electrophoresis and immunoelectrophoresis, and those containing the LC were purified by gel filtration on Sephadex G100 superfine (Pharmacia, Uppsala, Sweden). Light chain SAU was directly purified by gel filtration. Proteins CHEB, TRO, TRE and HAL were purified as previously described (Leboulleux et al., 1995).
Cathepsin B digestion
Digestion by cathepsin B (ICN Biomedicals, Orsay, France) was performed at 37°C on LC solutions at 1 mg/ml in 80 mM sodium acetate, 8 mM L-cystein, pH 5.0 (0.33 units per 10 µg LC). The reaction was stopped with 10 mM iodoacetamide. After various incubation times from 6 to 48 h, samples were frozen and analyzed on 12% SDSPAGE.
Proteolytic cleavages
Proteins (130 to 420 µg) were cleaved by trypsin in 0.1 M Tris buffer pH 8.5 supplemented with L-(tosylamido2-phenyl) ethylchloromethylketone-treated trypsin (Worthington, Freehold, NJ; enzyme:substrate ratio 1:50) for 6 h at 37°C. Staphylococcus aureus V8 protease (Boehringer, Mannheim, Germany) digestion was performed on 200 µg of protein in 0.025 M sodium phosphate buffer pH 7.8 (enzyme:substrate ratio 1:70) during 16 h at 25°C. Endoproteinase Asp-N from Pseudomonas fragi was purchased from Boehringer. Proteins (25 µg) were dissolved in 0.05 M sodium phosphate buffer pH 8.0 (enzyme:substrate ratio 1:50) and left to react during 18 h at 37°C. After each incubation, the medium was acidified by adding trifluoroacetic acid to pH 2.5. Digestion peptides were recovered by reverse-phase high performance liquid chromatography (HPLC) on a C8 Aquapore RP 300 column (220x4 mm, Brownlee) with a linear gradient of acetonitrile in 0.03% trifluoroacetic acid. Eluted peptides were detected by UV absorbance at 214 nm and stored at 20°C until sequence analysis.
Amino acid sequence determination
The amino acid sequences of the N-terminus (proteins HAL and SCH) and digestion peptides (proteins LEC, SAU and VAL) were determined by Edman degradation. Proteins or peptides were loaded on a polybrene treated glass fiber filter and sequencing was performed using a 470A Applied Biosystems (Foster City, CA) gas phase sequencer. Phenylthiohydantoin (PTH) amino acids were identified on-line with a 120A Applied Biosystems PTH-Analyser by reverse-phase-HPLC using a Brownlee PTH-C18 column (220x2.1 mm). All material and reagents used for sequencing were from Applied Biosystems. Sequences of complementary DNA corresponding to LCs CHEB, DEL, TRE and TRO had been determined previously (Aucouturier et al., 1993; Rocca et al., 1995
).
Sequence analysis
Amino acid sequences of LCs responsible for Fanconi's syndrome were compared with the Kabat databank (Kabat et al., 1991), using a program developed by Martin (1996). Because this databank contains many sequences of human LCs which are not secreted as free subunits, we also compared our results with a database including known monoclonal LCs from patients with plasma cell dyscrasias (F.Stevens, unpublished data), referred to here as the BenceJones databank. It is worth noting that sequences of AL-amyloidosis LCs are largely over-represented in this databank (51% of
chains) as compared with the normal incidence in pathology. The SUBIM program (Déret et al., 1995
) was used to determine the variability subgroups of LCs included in this study. The BLAST server at the National Center for Biotechnology Information (Altschul et al., 1990
) was used to search for similarities between V domain sequences responsible for Fanconi's syndrome and those deposited in the Brookhaven Protein Databank (PDB) (Bernstein et al., 1977
). Multiple pairwise alignments were performed using the FASTA algorithm (Pearson and Lipman, 1988
).
Molecular modeling
Because of the availability of known homologous 3D-structures in the PDB, only VI LCs responsible for Fanconi's syndrome were modeled, using the PROMOD automatic molecular modeling server (Peitsch, 1995
, 1996
), as previously described (Déret et al., 1997
). The structure with PDB code 2FGW (Eigenbrot et al., 1994
) was used as template for all Fanconi's syndrome LCs. The percentages of identity between pathogenic sequences and 2FGW is around 80%.
The PROCHECK software (Laskowski, 1993; Laskowski et al., 1993
) was used to validate the models by testing all the basic geometrical parameters. A model of the non-pathogenic LC V
I SAU was obtained as described above, using the crystallographic structure BRE (Schormann et al., 1995
) as a template.
Surface accessibility was calculated (Lee and Richards, 1971). The relative accessibility of each residue was obtained by dividing its corresponding accessibility with that of the same residue in an extended conformation (Richmond and Richards, 1978
).
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Results |
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The V regions of LEC and SCH were resistant to cathepsin B after an incubation time of 48 h (Figure 1), as previously described for CHEB, DEL, TRE and TRO (Leboulleux et al., 1995
). Complete and V domain of LC VAL were digested by cathepsin B, as previously shown for protein HAL (Leboulleux et al., 1995
); it is worth noting that the latter two were related with a Fanconi's syndrome associated with a cast nephropathy. The non-pathogenic protein SAU also displayed a significant resistance to proteolysis. Digestions by cathepsin B from ICN (Orsay, France) were extended to 48 h in order to obtain results comparable with those of Leboulleux et al. (1995) with cathepsin B purchased from Sigma (St Louis, MO).
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All LCs responsible for Fanconi's syndrome belong to the VI variability subgroup, except VAL which is a V
III LC. Comparisons of LCs with kappa germline gene sequences showed that the highest homologies were found with gene LCO2/O12 for CHEB, LEC, TRE and TRO, gene LCO8/O18 for DEL, HAL and non pathogenic LC SAU, and gene L6 for VAL. The limited N-terminal sequence of protein SCH did not allow assignment to a germline V segment.
As compared with other germline V segment sequences, the LCO2/O12 gene is featured by numerous additional serines (positions 28, 31, 56, 91 and 93); interestingly, while these residues are conserved or replaced with threonines in the two cases featuring the highest in vivo crystal accumulation (CHEB and TRE), they are replaced by asparagine at positions 28 and 31 in LEC (residues 91 and 93 could not be determined in the latter), and only S28 is substituted by N in TRO, which corresponds to a case with less abundant intracellular crystals.
Detailed analysis of sequences of Fanconi's syndrome revealed 14 unusual residues at several positions (Figure 2). Unusual residues were defined as occurring in less than 1% of compared V
sequences at the corresponding positions in the Kabat databank (Kabat et al., 1991
). They were equally frequent in the CDRs and FRs of the whole set of Fanconi's syndrome sequences. Results from comparison with the BenceJones databank are given in Table II
. The unusual residues are absent in germline sequences except for L94 (instead of I94 in Table II
) which was described in L10a and L25 sequences (Huber et al., 1993
). The number of unusual hydrophobic amino acids is the most apparent peculiarity of LCs from Fanconi's syndrome. In particular, a hydrophobic or non-polar residue is present at position 30 in four cases (CHEB, TRE, TRO and LEC). Structural implications of these residues will be analyzed below. In protein VAL, an unusual insertion of a lysine is found just beside another basic residue, R54.
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Molecular modeling: validation of models
Seventy-eight to 87% of the residues in the modeled structures are in favored regions on Ramachandran plots, as defined by Morris et al. (1992). In the LEC model, the residue at position 30 is located in a disallowed region; however, unusual phi and psi values for residue 30 were previously found in crystallographic structures WAT (Huang et al., 1994) and REI (Epp et al., 1974
). The residue at position 31 is located in a defavored region in CHEB, TRO and germline LCO2/O12 models, and in DEL crystallographic structure (A.Roussel, manuscript submitted). In all models and DEL crystallographic structure, A51 is also in a disallowed region; a high energy conformation for this residue was also described by Essen and Skerra (1994) in protein M29b. In Fanconi LC models, the value of the omega standard deviation is correct as compared with that of well refined structures, except for residues at positions 30 and 50 in LEC and SAU, respectively.
Surface accessibility
Residues of all studied models and structures with a relative accessibility over 60% are indicated in Figure 3. Figure 4
shows the molecular models of SAU, TRE and LEC V domains. Residue 30 in CDR-L1 is exposed to the solvent in models TRE, TRO and LEC but not in CHEB. However, F32 is exposed to the solvent in CHEB. Among the three Fanconi's syndrome LCs that do not form crystals, the two V
I display distinctive features: (i) a mutation at position 49 introducing a hydrophilic amino acid instead of a Tyr in all crystal-forming LCs. As found in the DEL crystallographic structure (A.Roussel, manuscript submitted), this mutation does not seem to influence the global conformation; and (ii) the absence of a significantly exposed residue in the CDR-L3 loop of DEL crystallographic structure. In the LCO8/O18 model, Y91 was found to be exposed to the solvent. In the DEL crystallographic structure, the presence of a non-bulky residue close to Y91 (H49 instead of Y49 in O8/O18) could explain the non-accessibility of this residue. In the SAU model, Y91 was found to be buried: neighbors at positions 49 and 50 are S and D, respectively. H49, in the DEL crystallographic structure, is buried as well as serine at the same position in LEC, whereas the usual tyrosine is exposed in the models of germline LCO2/O12, CHEB, TRE and TRO.
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Discussion |
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The precise pathophysiology of myeloma associated Fanconi's syndrome is still unknown. In a previous series of studies (Maldonado et al., 1975), crystal storage inside tubular cells and plasma cells was considered a hallmark of monoclonal LC-associated Fanconi's syndrome; overloading by these inclusions could explain the proximal tubule impairment as well as the slowly progressive nature of the tumor. Seryl and threonyl residues that featured the LCO2/O12 gene might favour crystallization through hydrogen bonding. More recently, we suggested that accumulation of crystals made up of a 107 amino acid fragment, corresponding to the kappa LC V domain in the endolysosomal compartment of proximal tubule cells, may be a main cause for toxic effects (Aucouturier et al., 1993
). Analysis of four cases (Leboulleux et al., 1995
) revealed that resistance of the V fragment to cellular catabolism by cathepsin B was a distinctive property of Fanconi LCs, and thus could explain the inability of cells to catabolize them. However, protein VAL was found to be digested by cathepsin B, which is unusual in Fanconi LCs. The finding of a strongly exposed lysine just after R54 might introduce a site of cleavage (Taralp et al., 1995
). This property raises the hypothesis that toxic mechanisms other than V region accumulation in endolysosomes may be implicated in the pathogenesis.
A peculiarity of DEL crystallographic structure is the absence of exposed residues in the CDR-L3 loop. This loop is involved in the formation of LC dimers (Kolmar et al., 1994; Stevens and Schiffer, 1995
), and thus an interactive residue in this region might impair dimerization and subsequent crystallization. The main feature of DEL structure is the non-conventional constant domain association which may be due to the lack of interchain disulfide bridge. The absence of disulfide bridge may also explain the susceptibility of Fanconi's LCs to proteases.
Certain Fanconi's syndrome cases do not show crystal accumulation; interestingly, in our series, two out of three such cases had a full-blown myeloma featuring severe osteolytic lesions, while the four cases with `classical' crystal-associated Fanconi's syndrome presented with a smoldering myeloma or a monoclonal gammapathy of undetermined significance. While proximal tubule impairment may occur in the absence of crystal formation, intracellular crystallization seems associated with the slowly proliferative character of the tumor. Indeed, it has been proposed that demonstration of crystalline inclusion inside bone marrow plasma cells may be a criterion for not treating the proliferative disease (Levine and Bernstein, 1985). It is possible that intracellular accumulation of crystals itself impairs the proliferation of plasma cells. Also, we believe that in several instances a selective proximal tubule impairment may remain unrecognized when it is associated with a high mass myeloma that dominates the clinical manifestations, which would explain why the Fanconi's syndrome has been essentially described in its classical crystal-storing form with mild plasma cell proliferation.
Results of structure analyses may be compared between four situations: (i) typical crystal-storing Fanconi's syndrome cases (CHEB, TRE, TRO), where the V fragment is always resistant to cathepsin B digestion; (ii) Fanconi's syndrome associated with cast nephropathy with crystals (HAL); (iii) Fanconi's syndrome without crystals with LC V fragment resistance to proteolysis (DEL, LEC); and (iv) Fanconi's syndrome without crystals and protease sensitivity of the LC (VAL).
All three LCs responsible for crystal-associated Fanconi's syndrome without casts (situation 1) derived from the V segment LCO2/O12 with a mutation introducing a non-polar residue in the CDR-L1 loop at position 30. Among BenceJones proteins, the LCO2/O12 gene was found to be expressed also in AL-amyloidosis, a disease characterized by a pseudo-crystallization of LC, and in one case of myeloma cast nephropathy (DRU; A.Solomon, unpublished data). Among LCs from amyloidosis patients, a few presented with a similar mutation (Table II). However, all five LCO2/O12-derived sequences that formed amyloid had an aspartic acid at position 50, a residue known to be significantly associated with amyloidogenic potential (Stevens et al., 1995
), while all LCO2/O12-derived Fanconi's syndrome light chains bear a non-polar (glycine or alanine) amino acid at this position. Furthermore, D50 is encoded by the germline sequence LCO8/O18, to which are related a number of amyloidogenic LCs, and this residue is mutated to an alanine in the Fanconi's syndrome LC DEL. Only one amyloid-associated residue (Stevens et al., 1995
), Q55, was found in proteins CHEB and TRO, as well as in protein LEC, while amyloidogenic LCs generally include several of them; moreover, the control kappa chain SAU also contains one amyloid-associated residue, D50. The role of hydrophobic side chains in the CDR-L1 loop might be significant and should be elucidated by directed mutagenesis on recombinant LCs. It might be a factor of protease resistance.
The partial amino acid sequence of HAL is clearly different, by the presence of Q24 which relates it to the LCO8/O18 gene and a charged residue, R, at position 30. Association of a cast nephropathy in patient HAL may result from the strong LC reactivity with the TammHorsfall protein, contrary to all other tested Fanconi LCs (Leboulleux et al., 1995). Possibly, the LC contact with the proximal tubule epithelium may be enhanced by tubule obstruction, resulting in increased toxicity in spite of the partial V domain sensitivity to cathepsin B. It will be of interest to test also the reactivity of LC LEC with TammHorsfall protein.
Our comparison of cases with distinct pathological presentations indicates that, although more homogeneous than other Ig LC diseases, the Fanconi's syndrome may be related to a variety of mechanisms. Obviously, increasing the number of known LC sequences would allow one to draw more definite hypotheses on the relationship between structure and pathogenic mechanisms.
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Acknowledgments |
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Notes |
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References |
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Received September 7, 1998; revised January 5, 1999; accepted January 21, 1999.