مجال
التميز
|
تميز دراسي وبحثي
|
|
|
البحوث المنشورة
|
|
البحث (1):
|
|
عنوان البحث:
|
Combined NGS
approaches identify mutations in the intraflagellar transport gene IFT140 in
skeletal ciliopathies with early progressive kidney disease
|
رابط إلى البحث
|
Link
|
تاريخ النشر:
|
April
2013
|
موجز عن البحث:
|
Ciliopathies are genetically
heterogeneous disorders characterized by variable expressivity and overlaps
between different disease entities. This is exemplified by the short
rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino
chondrodysplasia syndromes. These three syndromes are frequently caused by
mutations in intraflagellar transport (IFT) genes affecting the primary
cilia, which play a crucial role in skeletal and chondral development. Here,
we identified mutations in IFT140, an IFT complex A gene, in five Jeune
asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS)
families, by screening a cohort of 66 JATD/MSS patients using whole exome
sequencing and targeted resequencing of a customized ciliopathy gene panel.
We also found an enrichment of rare IFT140 alleles in JATD compared with
nonciliopathy diseases, implying putative modifier effects for certain
alleles. IFT140 patients presented with mild chest narrowing, but all had
end-stage renal failure under 13 years of age and retinal dystrophy when
examined for ocular dysfunction. This is consistent with the severe cystic
phenotype of Ift140 conditional knockout mice, and the higher level of Ift140
expression in kidney and retina compared with the skeleton at E15.5 in the
mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and
MSS). The present study strengthens the rationale for IFT140 screening in
skeletal ciliopathy spectrum patients that have kidney disease and/or retinal
dystrophy.
|
|
|
البحث (2):
|
|
عنوان البحث:
|
Defective
Presynaptic Choline Transport Underlies Hereditary Motor Neuropathy
|
رابط إلى البحث:
|
Link
|
تاريخ النشر:
|
November
2012
|
موجز عن البحث:
|
The neuromuscular junction (NMJ)
is a specialized synapse with a complex molecular architecture that provides
for reliable transmission between the nerve terminal and muscle fiber. Using
linkage analysis and whole-exome sequencing of DNA samples from subjects with
distal hereditary motor neuropathy type VII, we identified a mutation in
SLC5A7, which encodes the presynaptic choline transporter (CHT), a critical
determinant of synaptic acetylcholine synthesis and release at the NMJ. This
dominantly segregating SLC5A7 mutation truncates the encoded product just
beyond the final transmembrane domain, eliminating cytosolic-C-terminus
sequences known to regulate surface transporter trafficking.
Choline-transport assays in both transfected cells and monocytes from
affected individuals revealed significant reductions in
hemicholinium-3-sensitive choline uptake, a finding consistent with a
dominant-negative mode of action. The discovery of CHT dysfunction underlying
motor neuropathy identifies a biological basis for this group of conditions
and widens the spectrum of disorders that derive from impaired NMJ
transmission. Our findings compel consideration of mutations in SLC5A7 or its
functional partners in relation to unexplained motor neuronopathies.
|
|
|
البحث (3):
|
|
عنوان البحث:
|
Recessive HYDIN
Mutations Cause Primary Ciliary Dyskinesia without Randomization of
Left-Right Body Asymmetry
|
رابط إلى البحث:
|
Link
|
تاريخ النشر:
|
September
2012
|
موجز عن البحث:
|
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous
recessive disorder characterized by defective cilia and flagella motility.
Chronic destructive-airway disease is caused by abnormal respiratory-tract
mucociliary clearance. Abnormal propulsion of sperm flagella contributes to
male infertility. Genetic defects in most individuals affected by PCD cause
randomization of left-right body asymmetry; approximately half show situs
inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing
Hydin mutations was described as a recessive hydrocephalus model, we report
HYDIN mutations in PCD-affected persons without hydrocephalus. By homozygosity
mapping, we identified a PCD-associated locus, chromosomal region 16q21-q23,
which contains HYDIN. However, a nearly identical 360 kb paralogous segment
(HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In
three affected German siblings linked to HYDIN, we identified homozygous
c.3985G>T mutations that affect an evolutionary conserved splice acceptor
site and that subsequently cause aberrantly spliced transcripts predicting
premature protein termination in respiratory cells. Parallel whole-exome
sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T
(p.Lys307*), in six individuals from three Faroe Island PCD-affected families
that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an
ancestral founder mutation in this isolated population. We demonstrate by
electron microscopy tomography that, consistent with the effects of
loss-of-function mutations, HYDIN mutant respiratory cilia lack the C2b
projection of the central pair (CP) apparatus; similar findings were reported
in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy
demonstrated markedly reduced beating amplitudes of respiratory cilia and
stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons
had normal body composition because nodal cilia function is apparently not
dependent on the function of the CP apparatus.
|
|
|
البحث (4):
|
|
عنوان البحث:
|
Early diagnosis of
Werner’s syndrome using exome-wide sequencing in a single, atypical patient
|
رابط إلى البحث:
|
Link
|
تاريخ النشر:
|
Mars
2011
|
موجز عن البحث:
|
Genetic
diagnosis of inherited metabolic disease is conventionally achieved through
syndrome recognition and targeted gene sequencing, but many patients receive
no specific diagnosis. Next-generation sequencing allied to capture of
expressed sequences from genomic DNA now offers a powerful new diagnostic approach.
Barriers to routine diagnostic use include cost, and the complexity of
interpreting results arising from simultaneous identification of large
numbers of variants. We applied exome-wide sequencing to an individual,
16-year-old daughter of consanguineous parents with a novel syndrome of short
stature, severe insulin resistance, ptosis, and microcephaly. Pulldown of
expressed sequences from genomic DNA followed by massively parallel
sequencing was undertaken. Single nucleotide variants were called using
SAMtools prior to filtering based on sequence quality and existence in
control genomes and exomes. Of 485 genetic variants predicted to alter
protein sequence and absent from control data, 24 were homozygous in the
patient. One mutation – the p.Arg732X mutation in the WRN gene – has
previously been reported in Werner’s syndrome (WS). On re-evaluation of the
patient several early features of WS were detected including loss of fat from
the extremities and frontal hair thinning. Lymphoblastoid cells from the proband
exhibited a defective decatenation checkpoint, consistent with loss of WRN
activity. We have thus diagnosed WS some 15 years earlier than average,
permitting aggressive prophylactic therapy and screening for WS
complications, illustrating the potential of exome-wide sequencing to achieve
early diagnosis and change management of rare autosomal recessive disease,
even in individual patients of consanguineous parentage with apparently novel
syndromes.
|