3-M syndrome (MIM: 612921) is pre- and post-natal growth
restriction with relatively common group of disorders involving the skeletal
system, normal intelligence and distinctive facial features (1, 2). The three principle geneticists’ 3-MSBN who
first described the condition is Miller, McKusick, and Malvaux(3). 3-M syndrome
is characterized by prominent heels, normal loose joints and, in some cases,
radiological abnormal features (4). Affected males with 3-M syndrome have
hypogonadism, hypospadias and hypogonadism (5, 6). It is caused by pathogenic
mutations in encoding cullin 7 (CUL7 MIM: 609577) were subsequently
identified as the primary cause of 3-M syndrome that revealed a locus on
chromosome 6p21.1. Obscurin-like protein 1 (OBSL1 MIM: 610991) gene on long
arm of the chromosome 2 is the second 3-M syndrome locus (7, 8). Also, mutations
in coiled-coil domain containing protein 8 (CCDC8) have been reported as genetic
cause of 3M syndrome (9). CUL7 is a structural protein and OBSL1 encode
a cytoskeletal adaptor protein. Exactly function of CCDC8 gene undetermined.
However, the physical interaction of CCDC8 with CUL7 and OBSL1
have potential role in the growth-regulatory pathways (10).
3-M syndrome is an autosomal
recessive growth disorder. On the other hand, The function of OBSL1gene in
growth is doubtful. . It is a
cytoskeletal adaptor protein, like titin
and myomesin proteins, which localises to the perinuclear region to maintain
the structural integrity of the cells with linking cytoskeletal proteins (11,
12). However, recent studies established that individuals with 3-M syndrome and
OBSL1 mutations showed significant modulation of Insulin-like growth factor
binding protein 2 (IGFBP2 MIM: 146731) and IGFBP5 (MIM: 146734)
Moreover, OBSL1 gene has a broader role
in the CUL7 ligase signaling ubiquitination Pathway with controls Golgi and
dendrite morphogenesis (14).
Knockdown siRNA studies demonstrated
that OBSL1 mutations led to reduction in CUL7 expression. (15) Therefore, it is possible that CUL7–SCF
complex assistance with OBSL1 protean (16).
OBSL1 also acts to binding Mitogen-activated
protein kinase 11 (MAPK11) and MAPK14 in the cancer pathways (17).
Although, there is only elementary knowledge
of OBSL1 and it is clear that further characterization is required to elucidate
the function of OBSL1 and specifically its impact on the regulation of human growth
(18, 19). For OBSL1, approximately half of the patients have the same common
nonsense mutation (c.1273dupA, p.T425Nfs*40) (20). 3-M syndrome can be
diagnosed using well-established molecular basis and prevalence has been
demonstrated in many populations. 3-M syndrome prevalence and spectrum are
unknown in Iran.
In the present study, we identify
and report for the first time an unreported nonsense mutation on OBSL1 gene
in an Iranian family with 3-M syndrome.