Genetic defects: Nuclear envelopathies affecting the cell nucleus

The nuclear envelope is an important structure in the eukaryotic cell. It not only partitions the nucleus from the rest of the cell, but it has also been found in recent years to be involved in mitotic processes. The nuclear envelope is composed of the two-layer nuclear membrane and nuclear pore structures – all of which require proteins. Defects in the genes encoding these proteins have been termed nuclear envelopathies.

Genetic defects involved in nuclear envelopathies

In 2005, Somech et al. wrote an extensive review of what was known about nuclear envelopathies at the time for the journal Pediatric Research. At that time, four proteins were known to be mutated in these diseases: emerin, lamin A/C, lamin B receptor and MAN1, a lamin-associated protein encoded by the LEMD3 gene. By 2009, defects in the SUN proteins had also been implicated in disrupted nuclear position, and the ZMPST24 gene, which encodes a protein that processes lamin A, had been implicated in lamin-associated disorders.

Other recent additions to the list of nuclear envelope defects are the SYNE1 gene encoding Nesprin-1 and causing cerebellar ataxia, the TOR1A gene encoding TorsinA and causing dystonia, the AAAS gene encoding Aladin and causing triple A syndrome, and defects in the nuclear pore complex. Work in mice has also indicated that mitotic arrest deficient (MAD) proteins, which are associated with the nuclear pore, may cause defects in mitosis, allowing tumor cell growth.

Types of nuclear envelopathies


The most well known nuclear envelopathies are laminopathies – defects in the lamin A/C isoforms, which are encoded by the LMNA gene. The lamins form the lamina, a complex of intermediate filaments under the inner nuclear membrane that connect nuclear pore complexes. Some researchers, such as Broers et al. in 2006, differentiate laminopathies from nuclear envelopathies, defining the envelopathies as defects in the inner nuclear membrane and nuclear pore complex only. However, as the lamina is involved in the function and integrity of the cell nucleus, defects in the lamin proteins affect the nuclear envelope.

Laminopathies result in numerous types of disorders – at least a dozen have been named and recognized, including premature aging, muscular dystrophy, lipodystrophy and cardiovascular disorders. Defects in the lamin B receptors (encoded by the LMNB gene) cause chromatin disorders in blood granulocytes, termed the Pelger-Huet anomaly. This anomaly was first reported in 1928 by Pelger, and its dominant inherited nature was discovered a few years later by a pediatrician named Huet.


Emerin is encoded by the EMD gene. Defects in this gene are often termed emerinopathies. Defects in EMD and LMNA cause similar muscular dystrophic disorders. Emery-Dreifuss muscular dystrophy is an emerinopathy caused by X-linked recessive mutations in EMD.


The nuclear pore defects, called nucleoporinopathies, are related to Nup155, Nup62 and RanBP2, causing atrial fibrillation, infantile striatal necrosis and acute necrotizing encephalopathy, respectively. Triple A syndrome is a rare autosomal recessive nucleoporinopathy caused by mutations in AAAS that lead to adrenal failure.

Diagnosis and treatment

Nuclear envelopathies are congenital defects and as such require consultation with a genetic counselor for treatment options. Some of the mutations are inherited, yet others are de novo mutations (occurring spontaneously prior to or during embryological development). Genetic testing can pinpoint the exact cause of suspected nuclear envelopathy in many cases, which could then indicate treatment, but research is ongoing as to the best diagnosis and treatment options for each mutation and disorder.