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Driving forces in amyloidosis: How does a light chain make a heavy heart?

ABSTRACT: Light-chain amyloidosis (AL) is a fatal disorder wherein the immunoglobulin light chain misfolds and aggregates, leading to amyloid plaques in various organs. Patient-specific mutations in the light chain variable domain (V_L) are tightly linked to amyloidosis, but how these mutations drive AL is unknown. In recent work, Rottenaicher et al. analyze five mutations found in the V_L of a patient with cardiac AL. Their data suggest that decreased V_L stability and increased flexibility in the core of the V_L, caused by mutations outside of this core, could be key to aggregation and highlight the delicate balancing act required for antibody maturation to enable antigen recognition while not altering protein biophysics.

SUBMITTER: Otzen DE

PROVIDER: S-EPMC8191319 | biostudies-literature | 2021 Jan-Jun

REPOSITORIES: biostudies-literature

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Driving forces in amyloidosis: How does a light chain make a heavy heart?

Otzen Daniel E DE

The Journal of biological chemistry 20210101

Light-chain amyloidosis (AL) is a fatal disorder wherein the immunoglobulin light chain misfolds and aggregates, leading to amyloid plaques in various organs. Patient-specific mutations in the light chain variable domain (VL) are tightly linked to amyloidosis, but how these mutations drive AL is unknown. In recent work, Rottenaicher et al. analyze five mutations found in the VL of a patient with cardiac AL. Their data suggest that decreased VL stability and incre ...[more]

PMID: 34019874

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Project description:BackgroundSegmental duplication and deletion were implicated for a region containing the human immunoglobulin heavy chain variable (IGHV) gene segments, 1.9III/hv3005 (possible allelic variants of IGHV3-30) and hv3019b9 (a possible allelic variant of IGHV3-33). However, very little is known about the ranges of the duplication and the polymorphic region. This is mainly because of the difficulty associated with distinguishing between allelic and paralogous sequences in the IGHV region containing extensive repetitive sequences. Inability to separate the two parental haploid genomes in the subjects is another serious barrier. To address these issues, unique DNA sequence tags evenly distributed within and flanking the duplicated region implicated by the previous studies were selected. The selected tags in single sperm from six unrelated healthy donors were amplified by multiplex PCR followed by microarray detection. In this way, individual haplotypes of different parental origins in the sperm donors could be analyzed separately and precisely. The identified polymorphic region was further analyzed at the nucleotide sequence level using sequences from the three human genomic sequence assemblies in the database.ResultsA large polymorphic region was identified using the selected sequence tags. Four of the 12 haplotypes were shown to contain consecutively undetectable tags spanning in a variable range. Detailed analysis of sequences from the genomic sequence assemblies revealed two large duplicate sequence blocks of 24,696 bp and 24,387 bp, respectively, and an incomplete copy of 961 bp in this region. It contains up to 13 IGHV gene segments depending on haplotypes. A polymorphic region was found to be located within the duplicated blocks. The variants of this polymorphism unusually diverged at the nucleotide sequence level and in IGHV gene segment number, composition and organization, indicating a limited selection pressure in general. However, the divergence level within the gene segments is significantly different from that in the intergenic regions indicating that these regions may have been subject to different selection pressures and that the IGHV gene segments in this region are functionally important.ConclusionsNon-reciprocal genetic rearrangements associated with large duplicate sequence blocks could substantially contribute to the IGHV region diversity. Since the resulting polymorphisms may affect the number, composition and organization of the gene segments in this region, it may have significant impact on the function of the IGHV gene segment repertoire, antibody diversity, and therefore, the immune system. Because one of the gene segments, 3-30 (1.9III), is associated with autoimmune diseases, it could be of diagnostic significance to learn about the variants in the haplotypes by using the multiplex haplotype analysis system used in the present study with DNA sequence tags specific for the variants of all gene segments in this region.

Dataset Information

Driving forces in amyloidosis: How does a light chain make a heavy heart?

Publications

Driving forces in amyloidosis: How does a light chain make a heavy heart?

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