Sotos
syndrome is a relatively common neurologic disorder characterized by
prenatal and postnatal overgrowth, advanced bone maturation, large skull
with acromegalic features, and significant developmental delay. Most
cases are sporadic, but autosomal dominant inheritance has been
suggested in some instances and autosomal inheritance in a few rare
instances. Reports of balanced translocations have pointed to several
chromosomal sites as the location of a gene responsible for the
syndrome. One of these has led to the identification of mutations of a
nuclear hormone receptor cofactor as a major cause of this
syndrome.
Kurotaki
et al analyzed DNA from a patient with a de novo translocation 46,XX,t(5;8)(q35;q24.1)
that had been reported previously by Imaizumi
et al. From analysis of a series of overlapping clones, a contig, that
covered the break point, they identified a partial sequence that
corresponded to a gene originally cloned in mice, NSD1. They
then isolated and characterized the human NSD1 showing that it
encoded a protein of 2,696 amino acids that is expressed in many tissues
including fetal brain, skeletal muscle and kidney, and that the 5q35
breakpoint is located within NSD1.
The group next analyzed DNA from 38 patients with the clinical diagnosis
of Sotos syndrome. De novo point mutations that would predict truncated
gene products with loss of function were identified in four
individuals. Fluorescent in situ hybridization (FISH) analysis revealed
a common 2.2 Mb deletion in 18 and a smaller deletion in one of 30
patients in whom a suitable chromosomal spread was available. These
deletions included the entire NSD1 gene. In total, a loss of
function mutation or a deletion of NSD1 was found in 77% of
patients implicating haploinsufficiency of
NSD1 as a cause of Sotos syndrome.
NSD1
is thought to act as a co-activator or co-repressor of nuclear hormone
receptors, such as the androgen receptor, depending on the promoter
context of the target gene and the cellular context. In other words, in
one cell type NSD1 may interact with a combination of regulatory
factors unique to the cell type to activate a target gene, whereas it
may interact with another set of factors to inhibit expression of target
genes in another cell type. The mutations thus alter expression of
target genes in relevant tissues.
Clinically, the authors state that the identification of a deletion or
mutation of this mutated gene on chromosome 5 will sometimes help in the
diagnosis of Sotos syndrome.
Investigatively, the knowledge reported in
this article will eventually shed light on some of the underlying
mechanisms producing human mental retardation and physical growth.
First Editor’s
Comments:
Sotos syndrome has been considered to be a
relatively heterogeneous entity. The identification of the responsible
gene(s) will undoubtedly lead to a better definition of the syndrome and
a better understanding of the features observed.
Sotos syndrome can now be added to the growing list of disorders
with microdeletions in which fluorescent
probes are available to identify affected individuals.
In the last few years, identification of individuals with translocations
has been instrumental in identifying the genes responsible for many
genetic disorders. Sotos syndrome has been
considered to be sporadic, even though there were a few reports of
parent/child involvement. This discovery clearly confirms that an
abnormality in only one allele leads to the syndrome. As in other
microdeletions, the size of the deletion may
indicate how severely an individual is affected.
Second Editor’s
Comment:
The results reported in this paper argue strongly that Sotos syndrome is
caused by a partial loss of NSD1 function. The range of nuclear
receptors whose action is affected by NSD1 is not known, nor
are the target genes whose level of
expression are influenced by NSD1. Given the overgrowth features
of Sotos syndrome, one would conclude that
the relevant genes are involved in controlling growth and maturation,
probably at a very basic level. Moreover, one would expect that the
mutations lead to loss of co-activation of growth inhibiting genes, loss
of repression of growth promoting genes, or some combination of the
two. Questions still remain regarding which cell types are involved.
NSD1 is known to be expressed in the fetal brain, which
presumably explains the CNS manifestations, but the cells responsible
for the skeletal features are still not known.
William A. Horton, MD
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