Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype

Kathryn Volkening,Michael J Strong,Sali M K Farhan,Jian Wang,Robert A Hegele,Cheryl Leystra-Lantz,Jessica Kao,Lee Cyn Ang,Adam Mcintyre

doi:10.1007/s11010-021-04103-7

Abstract

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in LMNA, and two additional variants, one each in SETX (g.intron10-13delCTT) and FUS (p.Gly167_Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the FUS variant appears to be protective against the effects of the SETX and the LMNA variants on cell viability and may indicate loss of interaction of FUS with SETX and/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that targets motor neurons and commonly results in death within 2–5 years of diagnosis
In this study we have identified a family affected by amyotrophic lateral sclerosis (ALS), with several genotypes involving variants in ALSlinked genes SETX and Fused in sarcoma (FUS), and a variant in Lamin A (LMNA), in which the presence of all three variants is observed only in the patient with the ALS phenotype
This suggests that co-inheritance of variants is an important risk factor in developing ALS, and that these variants likely do not function in isolation but in more complex synergistic networks which may lead to disease

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that targets motor neurons and commonly results in death within 2–5 years of diagnosis. In this study we have identified a family affected by ALS, with several genotypes involving variants in ALSlinked genes SETX and FUS, and a variant in LMNA, in which the presence of all three variants is observed only in the patient with the ALS phenotype. This suggests that co-inheritance of variants is an important risk factor in developing ALS, and that these variants likely do not function in isolation but in more complex synergistic networks which may lead to disease. The lipodystrophy and cardiac phenotypes seen in this family were highly suggestive of a possible LMNA mutation while ALS mutations needed to be examined

Material and methods

Results and discussion

Compliance with ethical standards