Zhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0
https://doi.org/10.1186/s12881-018-0723-5

R ESEA R CH

Open AccessA homozygous G insertion in MPLKIP
leads to TTDN1 with the hypergonadotropic
hypogonadism symptom
Yi-Kun Zhou1*† , Xiao-Chun Yang2† , Yang Cao3 , Heng Su1 , Li Liu4 , Zhi Liang5* and Yun Zheng4*
From 29th International Conference on Genome Informatics
Yunnan, China. 3-5 December 2018

Abstract
Background: Trichothiodystrophy nonphotosensitive 1 (TTDN1) is a disease with mental retardation, brittle hair.
Some cases of the diseases are caused by mutations of the MPLKIP gene.
Methods: We carefully identified the clinic characteristics, the sulfur level and pattern of the hair shafts of a female
patient of with the symptom of hypergonadotropic hypogonadism, and of her parents and brother whose arehealthy. We also collected the blood sample of the patient and performed the exon sequencing. One G insertion in
MPLKIP was identified after analyzing the obtained exon sequencing profile. The G insertion sites in the patient, herparents and brother, were verified using Sanger sequencing. The G insertion in MPLKIP were compared to the dbSNP.
Results: The female patient of TTDN1 carries a homozygous G insertion (rs747470385) in the MPLKIP gene. The
parents and brother of the patient are heterozygous carriers of the same mutation, but are healthy. The hair shafts ofthe patient had a tiger-tail pattern with relatively low sulfur levels. To the best of our knowledge, this is the first reportthat autosomal recessive inheritance of the G insertion in the MPLKIP gene results in TTDN1.
Conclusion: Our results indicate that the homozygotic G insertion in MPLKIP results in the TTDN1 withhypergonadotropic hypogonadism, while heterozygous carriers of the same mutation have no symptoms andhealthy. These results provide novel insights into the association of mutations in MPLKIP and TTDN1 withhypergonadotropic hypogonadism.
Keywords: Trichothiodystrophy nonphotosensitive 1 (TTDN1), Hypergonadotropic hypogonadism, MPLKIP,
Mutation, Small Indel
Background
Trichothiodystrophy (TTD) is an autosomal recessive disorder of neuroectodermal origin. This condition is characterized by a cross-banding pattern, i.e. tiger-tail, underpolarized light and low sulfur content in the hair shafts,
which are associated with variable and neuroectodermal*Correspondence: yikunzhou22@sina.com; zhiliang1973@sina.com;
zhengyun5488@gmail.com† Yi-Kun Zhou and Xiao-Chun Yang contributed equally to this work.
1
Department of Endocrinology and Metabolism, First People’s Hospital of
Yunnan Province (The Affiliated Hospital of Kunming University of Science andTechnology), Kunming 650032, People’s Republic of China
5
Department of Information center, First People’s Hospital of Yunnan Province(The Affiliated Hospital of Kunming University of Science and Technology),
Kunming 650032, People’s Republic of China
Full list of author information is available at the end of the article

symptoms. The condition manifests with brittle hair,intellectual disability, dwarfism, decreased fertility, microcephaly, abnormal facial features, ichthyosis prematureaging, nail dystrophies, and a propensity for respiratory
infections [1]. TTD is divided into two types: photosensitive (TTD1-3) and nonphotosensitive (TTD4 or TTDN1).
Photosensitivity exists in about 50% of TTD patients,
which is due to reduced amounts of transcription/repair
factor IIH involved in global genome and transcription
repair [2, 3]. Mutations in the MPLKIP gene cause somecases of TTDN1.
MPLKIP is located on chromosome 7p14.1 and includes
two coding exons that encode a protein called M-phasespecific PLK1-interacting protein, which can interact with© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to theCreative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Zhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0

PLK1 protein. Based on the function of the PLK1 protein and its location in the nucleus, the MPLKIP protein
plays a role in regulating the cell cycle. It is ubiquitously expressed in epidermis, hair follicles, brain, heart,
liver, kidney, skeletal muscle, pancreas, lung, and placenta[4–6]. The precise function of MPLKIP has not yet been
determined, but clinical symptoms of TTDN1 result frommutation of the gene [4].

Results
Physical characteristics of the patient

A 16 year old girl in China with primary amenorrhea andmental retardation was sent to the endocrinology clinic
by her parents. The patient was born full term via spontaneous vaginal delivery. Her birth weight and length areunknown. Her parents are cousins related by blood. Whenthe patient was 7 years old in primary school, she wasobserved to have significant mental retardation. Patients
had no complaints of tetany, ostalgia, hearing loss, orhyposmia. Menarche did not occur until 16 years of age.
A small amount of bleeding due to an artificial menstrual
cycle induced by local doctors occurred for 5 months.
The heights of her father and mother were 171 and 154
cm, respectively. The development and intelligence of herelder brother was normal. There was no history of any
endocrine illness in other family members.
Upon physical examination, her blood pressure was
100/66 mmHg, temperature 36°C, pulse rate 82 beats/min,and respiratory rate 20 breaths/min (see Table 1). The
patient had a height of 150 cm (<3rd centile on the2009 Chinese Academy of Pediatrics growth chart) with aweight of 39 kg (Table 1). Arm span was 145 cm with an
upper/lower segment ratio of 0.9:1 (Table 1). There wasPage 24 of 31

a lack of secondary sexual characteristics Tanner BII and
PH I (Table 1). Bilateral cataracts were found (Table 1).
The oral cavity had no enamel hypoplasia. The neck was
not short with excess skin and no goiter. There were no
notable special facial features except sparse eyebrows andbrittle hair. Abnormal forearm carrying angles were notfound. The fifth middle phalanxes on their both hands
were short. Chvostek’s sign, Trousseau’s sign, and signs ofneuromuscular irritability were not present. Her skin was
normal with no UV light sensitivity or ichthyosis issues.
Testing revealed a follicle-stimulating hormone (FSH)of 127.4 mIU/ml (normal range: 3.5-12.5 mIU/ml), progesterone (PROG): 0.52 nmol/l (0.6-4.7 nmol/l), luteal
hormone (LH): 65.25 mIU/ml (2.4-12.6 mIU/ml), estradiol (E2) 18.35 pmol/l (45.4-854 pmol/l), prolactin (PRL):
17.3 ng/ml (3.4-24.1 ng/ml) and testosterone (TEST): 0.18
nmol/ml (0.16-1.33 nmol/ml) (see Table 1). Serum 25hydroxy vitamin D was 19.68 ng/ml (>30 ng/ml). Botharginine and levodopa stimulation tests for growth hormone were carried out, revealing normal growth hormone
responses to stimulation. Liver, renal, thyroid, coagulation, fasting plasma glucose, blood fat, and dynamic
cortisol level tests were normal. The serum alkaline phosphatase, calcium, phosphorus, 24 hr urinary calcium, andparathormone were within reference ranges. However,the 24 hr urinary phosphorus was 5.99 mmol/d (12.9-42mmol/d).
MRI of the hypophysis was normal. X-rays of the wrist
and hand suggested that skeletal age was around 12 years,
which did not correspond to chronological age. Doubleenergy x-ray bone density suggested osteoporosis (Z: -4.5).
Wechsler intelligence scale revealed her intelligence quotient was lower than 40 points. Electrocardiogram showed

Table 1 The physical characteristics of the patient
Characteristics

Value

Characteristics

Value

Age (year)

16

BMDb

Z: -4.5

GenderFemaleFSHb (3.5-12.5mIU/ml)

127.4

Height (cm)150a

LHb (2.4-12.6 mIU/ml)

65.25

Weight (kg)39

E2b (45.4-854 pmol/l)

18.35

Blood Pressure (mmHg)

100/6625 (OH) D3 (ng/ml)

19.68

Hair shaft

Tiger-tail patternIntelligence

< 40c

Pubes

Tanner I

Skeletal age (year)

12

BreastTanner II

The same symptoms in family

No

Cataracts

Bilateral

Family history

Her parents are cousins

Upper/lower

0.9:1

Sulfur level of hair

Lower than normald

primary amenorrhea

Two stimulation tests for GHb

NormalMenstruationa

The value is smaller than the 3rd centile on the 2009 Chinese Academy of Pediatrics Growth Chart
Abbreviations are BMD: Bone Mineral Density, FSH: Follicle-Stimulating Hormone, LH: Luteal hormone, E2: Estradiol, and GH: Growth Hormone
Value was based on Wechsler intelligence scaled
The value of patient is 1.905 mg/kg, which is significantly lower than that of normal group, i.e., mother: 4.177 mg/kg, father: 4.811 mg/kg, and a normal control: 4.62 mg/kg(P = 0.02, t-test)bcZhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0

sinus rhythm, and first degree a-v block and ultrasonic cardiogram were normal. B ultrasonic examination
showed that Liver, bile, pancreas, spleen and kidney werenormal and both the uterus (43 mm × 28 mm × 15 mm)
and ovaries (right 16 mm × 5 mm, left 14 mm × 4.5 mm)
were smaller and the endometrium was thin. Her hairshafts were examined by polarized light microscopy andhad a characteristic tiger-tail pattern (Fig. 1a), which was
not noticed in her mother’s hair (Fig. 1b). The sulfur levelof the hair measured by atomic emission spectrometry
was 1.905 mg/kg significantly lower than both parents
and a healthy control (patient: 1.905 mg/kg compared tomother: 4.177 mg/kg, father: 4.811 mg/kg, and a normal
control: 4.62 mg/kg) (P = 0.02, t-test).
Characterizing the genomic mutations of the patient

Chromosomal karyotyping revealed the patient had a normal female karyotype (46, XX). In order to acquire amolecular diagnosis, exon sequencing was performed forthe patient. After analyzing the exon sequencing profile,
we found a G insertion in the first exon of the MPLKIP
gene. We then confirmed the G insertion with Sanger
sequencing, for the patient, and her father, mother, andelder brother (see green boxes in Fig. 1c to f ). From Fig. 1c,
it could be seen that the Sanger sequencing of the patientis clear and has no minor peaks in the region. However,in the Sanger sequencing results of her mother, father
and brother, two nucleotides after the G insertion sites(in the shaded regions of Fig. 1d to f, respectively) haveminor or almost equal peaks, suggesting heterozygous
genotypes. To summarize, the patient is homozygous for
the G insertion, while her father, mother, and brother are
heterozygous carriers (see Fig. 1d to f ).
We carefully examined the G insertion in MPLKIP andfound that the G insertion locates immediately after the177th nucleotide in MPLKIP transcript (Fig. 1g). The
normal MPLKIP protein consists of 179 amino acids.
The G insertion leads to a significantly short aminoacid sequence with only 58 residuals, and the sequencechanges after the 32nd amino acid (see Fig. 1h). Thus,
the homozygous G insertion may lead to total deletion offunctional MPLKIP protein in the patient. We compared
the identified G insertion to the latest dbSNP (v150) using
UCSC Genome Browser and found that the G insertion isa reported SNP, rs747470385 (-/G) (Fig. 1i).
The protein-protein interaction network of MPLKIP

We investigated the functional roles of MPLKIP by examining its protein-protein interaction network as well. As
shown in Fig. 2a, MPLKIP serves as a bridge between the
RNA Polymerase II complex (left part) and many other cofactors. Among proteins interacting with MPLKIP, SBDS
encodes a highly conserved protein that plays an essential
role in ribosome biogenesis. SBDS protein interacts with

Page 25 of 31

elongation factor-like GTPase 1 to disassociate eukaryotic initiation factor 6 from the late cytoplasmic pre-60S
ribosomal subunit allowing assembly of the 80S subunit.
Mutations within SBDS are associated with the autosomal recessive disorder Shwachman-Bodian-Diamondsyndrome (or Shwachman-Diamond syndrome), which
is a rare congenital disorder characterized by exocrine
pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities and short stature. FAM120C encodes
a potential transmembrane protein and lies in a region
where mutations and deletions have been associated withintellectual disability and autism. Some of the symptoms
caused by mutations in SBDS and FAM120C, such as
short stature and intellectual disability, are similar toshown in our patient.
We then performed Gene Onotology (GO) and KEGG
pathway enrichment analysis for the interacting proteinsof MPLKIP in Fig. 2a using KOBAS2 [7]. As shownin Fig. 2b, these genes are significantly enriched inmany RNA Polymerase II related transcription GO terms,
such as Transcription elongation from RNA polymerase
II promoter, DNA-templated transcription, elongation,
and Transcription initiation from RNA polymerase IIpromoter, DNA-directed RNA polymerase II, holoenzyme, DNA-directed RNA polymerase complex, Nucleic
acid binding, and RNA polymerase II carboxy-terminal
domain kinase activity. In Fig. 2c, it is shown that thesegenes are enriched in transcription related pathways too,such as Basal transcription factors and Nucleotide excision repair. Mutations in genes on the nucleotide excision repair pathway are associated with diseases, suchas xeroderma pigmentosum (XP), Cockayne syndrome(CS) and trichothiodystrophy (TTD). In summary, theseresults suggest that the loss of MPLKIP caused by the
G insertion will disrupt the interactions between manyother co-factors and Pol II complex, and affect the Pol
II involved transcription activities, which contributed tosymptoms witnessed in the patient.
Treatments and consequences of the patients

Due to gonadal failure, the patient was initially given
0.5 mg estradiol valerate once a day. Low-dose oestrogenmonotherapy enabled normal breast and uterine development. She had a vitamin D deficiency (serum 25 hydroxyvitamin D was 19.68 ng/ml) with osteoporosis, althoughosteoporosis in this patient was probably one of the phenotypes of hypogonadism; therefore, oral calcitriol andcalcium carbonate were given at doses of 0.25 μg and
600 mg, respectively, once daily. Although she had a shortstature, her parents did not want to treat the problem, so
no treatments were given to correct her height.
The patient followed up with us after 3 months. Her breast
developed to Tanner BIII and B ultrasonic examination
showed both her uterus (61 mm×42 mm×26 mm)

Zhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0

Page 26 of 31

Fig. 1 The brittle hair of the patient and G insertion identified in the patient. a The typical alternating dark and light “tiger tail” banding was seen bypolarized light microscopy in hair of the patient. b The typical alternating dark and light “tiger tail” banding was not seen by polarized lightmicroscopy in hair of the patient’s mother. c to f The Sanger sequencing of the mutated region in MPLKIP for the patient, her mother, her father andher elder brother, respectively. g The position of the G insertion in the MPLKIP gene. Query is the sequence obtained in Sanger sequencing. Ref. is
the sequence of MPLKIP mRNA (NM_138701.3). h The amino acid sequences of wild type MPLKIP gene (top) and the mutated MPLKIP gene with theidentified G insertion. Only the first 58 amino acids of the wild type MPLKIP protein are shown. i The G insertion was examined in UCSC Genome
Browser to be compared to the dbSNP (v150). The G insertion in MPLKIP is rs747470385 (-/G), as indicated by the blue rectangle

Zhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0

Page 27 of 31

Fig. 2 The protein-protein interaction network of MPLKIP. a The proteins interacting with MPLKIP examined using STRING [22]. An edge between
two proteins (shown as nodes) means these two proteins are interacting proteins. Purple and azure edges stand for experimentally determinedinteractions and interactions from curated databases, respectively. Green, red, and blue edges stand for predicted interactions from geneneighborhood, gene fusions and gene co-occurrence, respectively. Light green and black edges stand for other interactions from text mining andco-expression, respectively. b Some of the enriched GO terms for genes in Part (a). c The enriched KEGG pathways for genes in Part (a)and ovaries (right one was 25 mm×16 mm, while
the left one was not clear) were bigger than before
and the thickness of endometrium went from thin
to 3 mm with estradiol increased to 330.6 pmol/L(normal range 45.4-854 pmol/L). Her bone mineraldensity did not increase with initial estradiol valerate
treatment and a short treatment course with calcitriol.
The patient was kept on oestrogen and vitamin D supplements and was advised to follow-up again after 3
months.

Zhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0

Discussion
The patient had a number of symptoms associated withendocrine disorders, including hypergonadotropic hypogonadism, short stature, and osteoporosis. Meanwhile, she
presented with distinct characteristics of mental retardation, brittle hair with a tiger-tail pattern and low sulfur level, and cataract without photosensitivity. Manycases reported that TTDN1 manifested decreased fertility
but hypergonadotropic hypogonadism confirmed ovarianlesions were the reason of gonad disorder in this paper.
The relationship between TTDN1 and MPLKIP wasreported in 2005 [4]. Only 14 cases were reported in[8–12] after the study of Nakabayashi et al. [4]. As summarized in Table 2, there are different special phenotypic
manifestations in addition to common symptoms thatderive from various genetic mutations of MPLKIP. The
homozygous splice mutation c.339 + 1G > A within MP
LKIP results in mitral regurgitation [8]. Heller et al. [10]reported that mutations at two different loci cause autism
spectrum disorder (see Table 2). Mutation c. 277delT
results in seizure disorders [10], and mutation c.505dupA
within the MPLKIP gene has been shown to cause severe
renal failure [9]. Swagemakers et al. [13] reported that
Pollitt syndrome patients, with mental and physical retardation and trichorrhexis nodosa, carry C326delA. Bottaet al. [11] reported several cases of axial hypotonia andreduced motor coordination due to deletions at four different loci, and several cases with failure to thrive, very
poor motor performances and speech due to deletions at
two different loci (see Table 1). Nakabayashi et al. [4] andPrzedborski et al. [14] reported that 187_188delGG causes
ataxia.
Although the disease with low incidences displays
many of the characteristics of endocrine disease, we
hope it can be easily recognized by endocrinologists.
This is the first report of autosomal recessive inheritance of the G insertion (rs747470385) and provides novel
insights into endocrine symptoms associated with hypergonadotropic hypogonadism. Although the relationshipbetween hypogonadism and the MPLKIP gene mutationis unclear, the gene plays a key role in regulating in cytokinesis and mitosis that may be a possible reason to explain
the relationship.
TTDN1 should be considered in patients with hypogonadism. Hair shafts should be examined by polarized
light microscopy and sulfur levels in the hair can be measured as a simple and convenient method for screening for
TTDN1.
The wild-type MPLKIP gene is translated into a protein with 179 residues. Insertion of G at base 177 strongly
shifts translation. Some termination codons occur in the
mutant, implying the mutant protein may significantly
differ from the wild-type protein. There are only shortpolypeptides of ≤ 58 residues if translated (see Fig. 1h).

Page 28 of 31

The homologous sequence of the mutant was not foundin the Uniprot database [15]. For the short polypeptides,
their secondary structures [16] and disorder sequence [17]predictions show the majority of the polypeptides arecoils. It implies the polypeptides could be very flexible
without any stable 3D structures. Therefore, the mutant
proteins tend to degrade quickly. Therefore, all clinicalsymptoms in the patient may result from loss of functionof the original protein. To summarize, the homozygous
G insertion (rs747470385) in her MPLKIP gene caused
trichothiodystrophy nonphotosensitive 1 (TTDN1) withhypergonadotropic hypogonadism.
Our results suggest the homozygous G insertion(rs747470385) could potentially be used as a genetic
method to screen patients with hypergonadotropic
hypogonadism for their diagnosis as TTDN1.

Conclusions
The contributions of this work are three folds. First,
our results indicate that the homozygotic G insertion(rs747470385) cause TTDN1. Second, the homozygotic G
insertion could potentially be used as a diagnostic marker
of TTDN1. Third, our results indicate that the heterozygous rs747470385 does not lead to TTDN1. However,
the marriage between heterozygous rs747470385 carriers
should be prevented to minimize the risk of sick offspring.

Methods
Physical and clinical examinations were performed forthe patient, her parents and her elder brother in theFirst People’s Hospital of Yunnan Province (The Kunhua
Affiliated Hospital of Kunming University of Scienceand Technology, abbreviated as FPHY). The sulfur levelof the hair was examined using inductively coupledplasma-atomic emission spectrometry at Kunming CTER
Trace Element Measurement Research Center, Kunming,
Yunnan, China.
The blood sample of the patient was collected in FPHY.
The DNA sample was extracted and used for DNA subtotal exon sequencing at the RunningGene Inc, Beijing,
China. The obtained exon sequencing profile had been
deposited into the NCBI SRA database and available
with the accession number SRR7427760. The obtained
sequencing profile was aligned to human genome (hg38)
with Bowtie2 [18]. The mutations were analyzed using
SAMTools [19] and BCFTools [20] from the alignment
results of Bowtie2.
The G insertion in the patient, her mother, father, andelder brother, were verified using Sanger sequencing withthe forward primer of CTGGAGTAGGAGCCAGGGT
and reverse primer of GGAGGGCCGGTTGATACAG.
After examining results of Sanger sequencing, a homozygous G insertion was found in the first exon of the
MPLKIP gene of the patient. Heterozygous G insertions

Zhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0

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Table 2 A summary of reported patients with mutations in the MPLKIP gene and clinical features
Country

Variation

Type

PS

HA

FD

MR

HG

O/O

CT

SS

Particularity

Ref.

Pakistanc.339 +1G > A

Splice

N

Y

Y

Y

NA

NA

Y

Y

Mitralregurgitation[7]

Caucasianc.2T>C (initiation codon)

N

Y

Y

Y

NA

Y

N

N

Autism spectrum
disorder[9]

CaucasianDeletion of ∼120kb;
c.227delG

Deletion

N

Y

Y

Y

NA

Y

Y

Y

Aortic arch withaberrant leftsubclavian artery[9]

Caucasianc.277delT; Deletion of∼92 kb

Deletion

N

Y

Y

NA

NA

NA

NA

Y

Atrialseptal defect;
pulmonic stenosis[9]

Caucasian

4 bp insertion & deletion of∼5kb starting at c.279

Insertion &deletion

Y

Y

Y

Y

NA

NA

NA

Y

Autism spectrum
disorder; epilepsy
with grand mal
seizures[9]

Israelc.505dupA mutation

Duplication

N

Y

NA

Y

Y

NA

N

Renal failure,splenomegaly[8]Netherlands

c.326delA

Deletion

NA?

Y?

NA

Y?

NA

NA

NA

NA

NA

[12]

Italy

Deletion of 11-31kb

Deletion

N

Y

NA

NA

NA

NA

NA

Y

Axial hypotonia
andreducedmotor
coordination

[10]

Italy

c.148_152delCAC AC

Deletion

N

Y

NA

Y

NA

NA

NA

Y

Failure to thrive,
very poor motor
performancesand speech

[10]

Italy

c.277delTc.148_15
2delCACAC

Deletion

N

Y

NA

NA

NA

NA

NA

Y

Axial hypotonia
andreducedmotor
coordination[10]

Kuwait (Indian)c.229delC

Deletion

N

Y

NA

Y

NA

NA

NA

Y

Failure to thrive,
very poor motor
performancesand speech

[10]

Iraq

Deletion of at least
150 kb

Deletion

N

Y

NA

NA

NA

NA

NA

Y

Axial hypotonia
andreducedmotor
coordination[10]

Netherlandsc.277delT

Deletion

N

Y

NA

NA

NA

NA

NA

Y

Axial hypotonia
andreducedmotor
coordination

[10]

Italy

partial exon 1 and entire
exon 2

Deletion

N

Y

NA

Y

NA

NA

NA

Y

Severe nervous
systemimpairment[5]

Morocco187_188delGG

Deletion

N

Y

Y

Y

Y

Y

NA

Y

Ataxia[5, 13]Amishc.480A>G

A ->G

NA

Y

NA

Y

Y

NA

NA

Y

Peru

{arr[hg19]7p14.1(40,140,770-40,265,451)x0}

a 125 kb
homozygous
deletion

NA

Y

Y

Y

NA

NA

NA

Y

China

rs747470385

-/G

N

Y

N

Y

Y

Y

Y

Y

[5]
Glutaric Aciduria
type 3

[11]

This
study

The abbreviations of the titles of the columns are PS: Photosensitivity, HA: Hair Abnormality, FD: Facial deformity, MR: Mental Retardation, HG: Hypogenadism, O/O:
Osteoporosis/Osteopenia, CT: Cataract, and SS: Short Stature

at the same positions were found in the parents andbrother of the patient. The obtained G insertion wascompared to the latest dbSNP using the UCSC Genome
Browser [21].
The protein-protein interaction networks of MPLKIP
was examined by using STRING [22]. A minimum

required interaction score of 0.4 and the second shell withno more than 20 interactors were used when searching
the protein “MPLKIP” in the species of “Homo sapiens” in STRING. The enriched Gene Ontology terms and
KEGG pathways of proteins interacting with MPLKIP
were analyzed by using KOBAS2 [7].

Zhou et al. BMC Medical Genetics 2018, 19(Suppl 1):0

Abbreviations
BMD: Bone Mineral Density; CS: Cockayne syndrome; E2: Estradiol; FSH:
Follicle-Stimulating Hormone; GH: Growth Hormone; GO: Gene Onotology; LH:
Luteal Hormone; MRI: Magnetic Resonance Imaging; PRL: Prolactin; PROG:
progesterone; TEST: Testosterone; TTD: trichothiodystrophy; TTDN1:
trichothiodystrophy nonphotosensitive 1; XP: xeroderma pigmentosum
Acknowledgements
Not applicable.
Funding
This work was funded by the two grants of National Natural Science
Foundations of China (number 81660146) and a Health System Academic
Leader Project of Yunnan province (D-201661) to YZhou; and by two grants of
National Natural Science Foundations of China (numbers 31460295 and31760314) to YZheng; and by the grant of National Natural Science
Foundations of China (number 31401130) to YC. Publication of this article wassponsored by National Natural Science Foundations of China (number
81660146) grant.
Availability of data and materials
The one obtained exon sequencing profile had been deposited into the NCBISRA database and available with the accession number SRR7427760.
About this supplement
This article has been published as part of BMC Medical Genetics Volume 19
Supplement 1, 2018: Proceedings of the 29th International Conference on Genome
Informatics (GIW 2018): medical genetics. The full contents of the supplement
are available online at https://bmcmedgenet.biomedcentral.com/articles/
supplements/volume-19-supplement-1.
Authors’ contributions
YKZ, ZL, and YZ conceived and designed the research. YKZ, XY, YC, ZL, and HS
performed the physical and clinical examinations for the patient. YKZ collected
the blood samples for the patient, her mother, father and brother. YKZ, YC andZL read the related literature. YZ and LL designed the computational pipeline
for analyzing exon sequencing profile and Sanger sequencing results. ZL, YC,
LL, and YZ analyzed the exon sequencing profile and Sanger sequencing
results. YKZ and YZ wrote the manuscript. All authors have read and approved
the final manuscript.
Ethics approval and consent to participate
The study was approved by the Medicine Ethics Committee of The First
People’s Hospital of Yunnan Province that is composed of 17 members,
including experts of laws, scientists and clinicians with relevant expertise. The
patient, her parents and brother, agreed on the research and the publicationof the current work.
Consent for publication
The patient, her parents and brother, agreed on the research and the
publication of the current work.
Competing interests
The authors declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.
Author details
1 Department of Endocrinology and Metabolism, First People’s Hospital of
Yunnan Province (The Affiliated Hospital of Kunming University of Science andTechnology), Kunming 650032, People’s Republic of China. 2 Department ofOphthalmology, First People’s Hospital of Yunnan Province (The Kunhua
Affiliated Hospital of Kunming University of Science and Technology),
Kunming 650032, People’s Republic of China. 3 Center of Growth, Metabolism
and Aging, Key Lab of Bio-Resources and Eco-Environment of Ministry of
Education, College of Life Sciences, Sichuan University, Chengdu 610064,
People’s Republic of China. 4 Yunnan Key Laboratory of Primate Biomedical
Research, Institute of Primate Translational Medicine, Kunming University of
Science and Technology, Kunming 650500, People’s Republic of China.

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5 Department of Information center, First People’s Hospital of Yunnan Province(The Affiliated Hospital of Kunming University of Science and Technology),
Kunming 650032, People’s Republic of China.

Published: 31 December 2018
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