The detection of mutations in the LMNA gene in laminopathies
, 1. Introduction
Monogenic diseases are diseases that occur due to a mutation in one single gene in all cells of
the body, which can be autosomal dominant, autosomal recessive, X-linked or Y-linked.
Dominant monogenic diseases involve damage to only one allele of either maternal or
paternal chromosomal origin and recessive ones involve damage to both alleles of both
parental origin [1]. Mutations are errors in DNA that can occur during DNA replication, DNA
recombination or DNA repair. These mutations can either be locally or large scaled. Local
DNA changes are also called point mutations and can vary from substitution of one base pair
for another, to the insertion or deletion of one base pair to the chain [2].
Laminopathies are disorders caused by point mutations in the LMNA gene. There are four
groups of laminopathies affecting either striated muscle, adipose tissue, peripheral nerve, or
multiple systems. The mutations in the LMNA gene lead to abnormal lamin synthesis. Lamins
are type V intermediate filament proteins and are an important structure of the inner nuclear
lamina to maintain nuclear structure and function. Lamins can be divided into two groups; A-
type and B-type. A-type lamins are coded by LMNA, so in laminopathies changes can be seen
in A-type lamins, as the mutation occurs in the LMNA gene. When A-type lamins are not
expressed in cells, the nuclei will be shaped differently, the nuclear envelope cracks and
nuclear pore complexes start to cluster [3].
There are different types of mutations that can occur in DNA, in this study, the focus is on
mutations of R453 and R482 in the LMNA gene. Previous research showed that mutations in
R482W cause familial partial lipodystrophy (FPLD), which means that the patients have
irregular fat distribution. After birth, normal fat distribution occurs, but from puberty, they
lose fat from several regions, and extra fat will be deposited within others. Mutations in
R453W cause Emery-Dreifuss muscular dystrophy (EDMD-AD), which causes regional,
progressing skeletal muscle wasting and cardiomyopathy with conduction blockage [4].
At this point there is no cure for laminopathies, as there is still not enough knowledge of the
background of the diseases. Simple gene therapy is not suitable as the mutations are too
complex, the main challenge in this is the neutralisation of the mutant allele without
disturbing normal gene expression [5]. A lot of research is going on and, several cures were
tested on mice. Nowadays only supportive care is available. However, identification of
2
, 1. Introduction
Monogenic diseases are diseases that occur due to a mutation in one single gene in all cells of
the body, which can be autosomal dominant, autosomal recessive, X-linked or Y-linked.
Dominant monogenic diseases involve damage to only one allele of either maternal or
paternal chromosomal origin and recessive ones involve damage to both alleles of both
parental origin [1]. Mutations are errors in DNA that can occur during DNA replication, DNA
recombination or DNA repair. These mutations can either be locally or large scaled. Local
DNA changes are also called point mutations and can vary from substitution of one base pair
for another, to the insertion or deletion of one base pair to the chain [2].
Laminopathies are disorders caused by point mutations in the LMNA gene. There are four
groups of laminopathies affecting either striated muscle, adipose tissue, peripheral nerve, or
multiple systems. The mutations in the LMNA gene lead to abnormal lamin synthesis. Lamins
are type V intermediate filament proteins and are an important structure of the inner nuclear
lamina to maintain nuclear structure and function. Lamins can be divided into two groups; A-
type and B-type. A-type lamins are coded by LMNA, so in laminopathies changes can be seen
in A-type lamins, as the mutation occurs in the LMNA gene. When A-type lamins are not
expressed in cells, the nuclei will be shaped differently, the nuclear envelope cracks and
nuclear pore complexes start to cluster [3].
There are different types of mutations that can occur in DNA, in this study, the focus is on
mutations of R453 and R482 in the LMNA gene. Previous research showed that mutations in
R482W cause familial partial lipodystrophy (FPLD), which means that the patients have
irregular fat distribution. After birth, normal fat distribution occurs, but from puberty, they
lose fat from several regions, and extra fat will be deposited within others. Mutations in
R453W cause Emery-Dreifuss muscular dystrophy (EDMD-AD), which causes regional,
progressing skeletal muscle wasting and cardiomyopathy with conduction blockage [4].
At this point there is no cure for laminopathies, as there is still not enough knowledge of the
background of the diseases. Simple gene therapy is not suitable as the mutations are too
complex, the main challenge in this is the neutralisation of the mutant allele without
disturbing normal gene expression [5]. A lot of research is going on and, several cures were
tested on mice. Nowadays only supportive care is available. However, identification of
2
