ISSN 1022-7954, Russian Journal of Genetics, 2016, Vol. 52, No. 10, pp. 1086–1093. © Pleiades Publishing, Inc., 2016.
Original Russian Text © N.R. Maksimova, A.N. Nogovicina, Kh.A. Kurtanov, E.I. Alekseeva, 2016, published in Genetika, 2016, Vol. 52, No. 10, pp. 1194–1201.
Population Frequency and Age of Mutation G5741→A in Gene NBAS
which is a Cause of SOPH Syndrome in Sakha (Yakutia) Republic
N. R. Maksimova
, A. N. Nogovicina
, Kh. A. Kurtanov
, and E. I. Alekseeva
Ammosov North-Eastern Federal University, Yakutsk, 677000 Russia
Yakut Scientific Center of Complex Medical Problems, Yakutsk, 677000 Russia
Received November 16, 2015
Abstract—SOPH syndrome (Short stature with Optic nerve atrophy and Pelger–Huët anomaly syndrome,
OMIM#614800) is an autosomal recessive hereditary disease characterized by the following main clinical
symptoms: postnatal hypoplasia, proportionately short stature, facial dysmorphism, micromelia of feet and
hands, limp and loose skin, optic nerve atrophy, and Pelger–Huët anomaly of neutrophils. For the first time,
this disease was described in Yakuts. The molecular-genetic study showed that its cause in Yakuts is mutation
G5741→A in gene NBAS. On the basis of disequilibrium analysis for linkage of ten microsatellite markers
flanking the NBAS gene with the disease, the haplotype of the founder chromosome was determined. The age
of the mutation in Yakutia was estimated to be about 804 ± 140 years. The frequency of heterozygous carriers
of mutation G5741→A (R1914H) in gene NBAS was found, which averaged 13 per 1000 healthy Yakuts.
Keywords: short stature syndrome with optic nerve atrophy and Pelger–Huët anomaly, Yakuts, NBAS, genetic
SOPH syndrome is an autosomal recessive heredi-
tary disease characterized by the following main clini-
cal symptoms: postnatal hypoplasia, proportionately
short stature, facial dysmorphism, micromelia of feet
and hands, limp and loose skin, cone dysfunction with
secondary optic nerve atrophy, and Pelger–Huët
anomaly of neutrophils . The syndrome was first
clinically described in 2010 in patients of Yakut
nationality. The new disease was called SOPH syn-
drome (Short stature with Optic atrophy and Pelger–
Huët anomaly syndrome) and included in the interna-
tional database OMIM (http://www.ncbi.nlm.nih.
gov/omim/) under no. 614800. Molecular genetic
analysis revealed the cause of SOPH syndrome, muta-
tion G5741→A (R1914H) in the NBAS protein gene
amplified in neuroblastoma . The frequency of the
disease is 1 per 10000 Yakuts.
The Republic of Sakha (Yakutia) is characterized
by a high incidence of hereditary diseases, high accu-
mulation of which in the Yakut population is due to
the founder effect (hereditary enzymopenic methe-
moglobinemia type 1, 3-M syndrome, spinocerebellar
ataxia type 1, oculopharyngeal myodystrophy, and
myotonic dystrophy) [2–6].
The purpose of this study is to define the age of
mutation G5741→A (R1914H) in the NBAS protein
gene amplified in neuroblastoma and estimate its car-
rier frequency in Yakuts and other groups of ethnically
and geographically close populations.
MATERIALS AND METHODS
To identify alleles associated with the disease and
estimate the age of the mutation, DNA samples of 32
patients and 27 healthy relatives from 29 Yakut fami-
lies with SOPH syndrome were used. To investigate
the frequency of heterozygous carriers of mutation
G5741→A (R1914H) in gene NBAS and determine the
population allele frequencies of the markers selected
for the study of the age of the mutation, DNA samples
from 307 healthy Yakuts, 100 Russian living in Yaku-
tia, and 100 Japanese from Japan were used. All indi-
viduals see themselves as representatives of indigenous
ethnic groups. All DNA samples were obtained with
informed consent of the test groups.
Amplification of necessary DNA fragments was
carried out by PCR using an MJ Research PTC-100
programmable thermal cycler in a volume of 25 μL of
PCR reaction mixture. Analysis of haplotypes of chromo-
somes carrying mutation G5741→A (R1914H) in gene
NBAS was carried out using ten microsatellite markers
flanking gene NBAS in the domain of 11.8 cM according to
the Marshfield map (http://www.ncbi.nlm.nih.gov). All
markers were selected via online databases of UCSC
Genome Browser on Human (http://genome.ucsc.