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been described, although these appear to be exceedingly rare.
Impaired intracellular 5’-deiodination of T4 to T3 has also
patient has been described with a deletion in this gene [13].
are TH cell membrane transporter (MCT8) defects. One Israeli
with only a few cases to date reported since 2011. Also described
We then studied the primary defect in
(THRA) mutations have been reported but are far more rare,
cause of reduced sensitivity to thyroid hormone. THR alpha
Although most common, THRB mutations are not the only
codon severely inhibit T3-mediated activation of the receptor.
to as the His-Phe switch. Mutations that disrupt this specific
creates an essential functional component of the protein referred
codon 435 is particularly critical for receptor function since it
[1]. More specifically, Hassan and co-authors [15] reported that
interaction with one or more cofactors involved in TH action
have been reported to cause either reduced affinity or abnormal
mutations described so far are located. Mutations in this region
ligand-binding domain of the receptor where virtually all THRB
known, codon 435 is located in the gene region coding for the
As both the H antigen and CD15 incor-
which this specific mutation causes receptor dysfunction is not
family [Table 2, Figure 1B]. While the precise mechanism by
segregated perfectly with diagnostic clinical findings in this large
ously reported in RTH-β patients [9,10,14] and the mutation co-
three different mutations in the same codon have been previ-
formed, it is highly likely that this mutation was causal, since
Muslim family. Although functional studies were not per-
We identified one novel mutation (p.His435Arg) in an Arab
clusters [Figure 1A].
mutation (p.His435Arg), were located within two of these three
tions [1]. In our study, all of the mutations, including the novel
CpG nucleotides and thus prone to single nucleotide substitu-
the receptor, clustered into three hot spots, which are rich in
THRB gene region coding for the ligand-binding domain of
All previously reported causal mutations are located in the
very severe phenotypes [1].
reported, but is exceedingly rare and typically associated with
all multi-generational families. Recessive inheritance has been
lence of consanguinity, inheritance was autosomal dominant in
despite the fact that some Israeli populations have a high preva-
these ethnic groups. Consistent with most previous reports, and
single extended family, excluding a founder mutation in any of
reports [12]. Each of the inherited mutations was limited to a
de-novo (p.Pro453Ser, p.Leu328Ser), consistent with previous
disease prevalence. Two of the eight THRB mutations were
(20% Arab Muslim) and does not suggest any ethnic bias in
and six Jewish, reflects the population make-up of the country
The ethnic background of affected families, two Arab Muslim
ders are equally affected (P = 0.27), as previously reported [1].
which is not significantly different from expected if both gen-
Sixty-two percent of affected individuals were females,
proven RSTH [12,13].
lished case reports described patients in Israel with genetically
here, to the best of our knowledge, only two previously pub-
EDITORIALS EDITORIALS PID may provide useful insights and email: etzioni@rambam.health.gov.il fax: (972-4) 777-4499 phone: (972-4) 777-4411 Campus, Haifa 31096, Israel Ruth Children’s Hospital, Rambam Healthcare Dr. A. Etzioni Correspondence preparing this manuscript Rechavi, and Prof. Somech for their help in I would like to thank Prof. Shiloh, Prof. Acknowledgement health and diseases. to the study of the endosome function in complement experimenta
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2. Sharma P, Mukherjee A, Karunanithi S, et al. G, Lantsberg S. Detection of disseminated 6. Wilkinson MD, Fulham MJ, McCaughan BC, ability. Whenever possible, data were corroborated by review
Potential role of 18F-FDG PET/CT in patients with aspergillosis on FDG PET-CT in a patient with Constable CJ. Invasive aspergillosis mimicking of medical records. Table 1. THRB gene mutations identified in eight patients
fungal infections. AJR Am J Roentgenol 2014; 203: acute lymphoblastic leukemia. IMAJ 2018; 20: stage IIIA non-small-cell lung cancer on FDG Mutation Exon Family
180-9. 717-9. positron emission tomography. Clin Nucl Med The questionnaire was divided into two main sections. The name number DNA sequence symbol Inheritance Reference
3. Franzius C, Biermann M, Hülskamp G, et al. 5. Kim JY, Yoo JW, Oh M, et al. 18F-fluoro-2- 2003; 28: 234-5. first included questions related to pregnancy, such as miscar- ...cttcgcgctgctgtg-C/T- AD
Therapy monitoring in aspergillosis using F-18 deoxy-D-glucose positron emission tomography/ 7. Baxter CG, Bishop P, Low SE, Baiden-Amissah riages, complications, thyroid-directed treatments, gestational p.Arg320Cys 9 gctatgacccagaaa… 8 Adams et al. [22]
FDG positron emission tomography. Clin Nucl computed tomography findings are different K, Denning DW. Pulmonary aspergillosis: an
Med 2001; 26: 232-3. between invasive and noninvasive pulmonary alternative diagnosis to lung cancer after positive week, and birth weight. Infants with birth weight below the p.Arg320Leu 9 …ttcgcgctgctgtgc-G/T- 4 AD Adams et al. [22]
4. Hod N, Anconina R, Levin D, Tiktinsky E, Ezroh aspergillosis. J Comput Assist Tomogr 2013; 37: [18F]FDG positron emission tomography. Thorax 10th percentile for gestational age were considered small for ctatgacccagaaag…
Kazap D, Levi I, Zektser M, Stavi V, Sebbag 596-601. 2011; 66: 638-40. gestational age (SGA) [8]. The second part addressed main p.Leu328Ser 9 …cagaaagtgagactt- 5 de-novo Grace et al. [23]
T/C-aaccttgaatgggga...
complications in the neonatal period and early childhood, p.Arg338Trp 9 …gaaatggcagtgaca-C/ 2 AD Adams et al. [22]
Capsule including phototherapy suggesting significant jaundice, and the T-ggggccagctgaaaa...
need for evaluation or intervention due to developmental delay. (p.His435Arg)* 10 ...tgataggagcctgcc- 7 AD
A/G-tgccagccgcttcct…
Role of stem cell-like memory t cells in systemic lupus erythematosus p.Arg438His 10 ...cctgccatgccagcc-G/A- 6 AD Adams et al. [22] and
131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Magenta
131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Yellow
Stem cell-like memory T (Tscm) cells are long‐lived memory derived Tfh cells to help B cells was analyzed by measuring RESULTS cttcctgcacatgaa… Refetoff, Dumitrescu [24]
#131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Black
131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Cyan
T cells that have multipotent capacity to differentiate antibody secretion. The percentages of CD 4+ and CD8+ THRB MuTATIOnS p.Pro453Ser 10 ...acagaactcttcccc-C/T- 1 de-novo Adams et al. [22]
ctttgttcttggaag...
into different subsets. However, the role of Tscm cells in Tscm cells among the naive CD4+/CD8+ or total CD4+ T cell Based on hormone analysis and clinical findings reported in p.Pro453Thr 10 ...acagaactcttcccc-C/A- 3 AD Adams et al. [22] and
autoimmune diseases remains unclear. lee et al. performed populations were significantly higher in SLE patients than in the patient referrals, 19 probands were invited for evaluation ctttgttcttggaag… Refetoff, Dumitrescu [24]
phenotypic studies to identify Tscm cells in patients HCs. Stimulated Tscm cells from SLE patients could replenish for possible RSTH. In eight, a careful review of all available AD = autosomal dominant inheritance
experiencing systemic lupus erythematosus (SLE). CD4+ and themselves and differentiate into other T lymphocyte subsets, data, including that obtained during evaluation for this study, *The novel THRB gene mutation is in bold
CD8+ Tscm cells were identified in SLE patients and healthy including Tfh cells upon stimulation with T cell receptor. excluded this diagnosis. In three, the diagnosis of subclinical
controls (HCs). In in vitro culture systems, CD4+ Tscm cells Production of T cell factor 1, which is an inducer of Tfh, was hypothyroidism was confirmed, with normalization of FT4, figure 1. [A] Graphic representation of the coding exons of the thyroid hormone
receptor-beta gene (THRB) showing the alternatively spliced regions (β1 and β2), the
were induced to differentiate into subsets of T cells, including also increased. The differentiated Tfh cells increased antibody FT3, and TSH following thyroid hormone replacement. In five, three mutations clusters and the approximate location of the eight mutations identified
follicular helper T (Tfh) cells, and cytokine production patterns production by autologous B cells. in this study. The figure is modified from Dumitrescu AM, Refetoff S. The syndromes of
were assessed after stimulation. After confirming induction of Arthritis Rheumatol 2018; 70: 1459 previous thyroid function tests were reported to be within the reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013; 1830: 3987-4003
transcription factors for Tfh cells, the capacity of CD4+ Tscm‐ Eitan Israeli normal range. One patient elected not to participate in the study. [1] [B] Pedigree of family 7. Circles indicate females, squares indicate males. Diagonal
In the 10 patients included in the study, all THRB coding line through symbol indicates that the subject was deceased at the time of the study.
exons and intron-exon boundaries were sequenced. No muta- Double lines connecting married couples indicate a first-cousin marriage. Thick arrow
Capsule tions were found in two patients, and further investigation of indicates the proband. Roman numerals indicate generation. Individuals who were
both showed clear evidence of a pituitary tumor on pituitary- included in the study are numbered consecutively in each generation (number within
directed magnetic resonance imaging, strongly suggesting the symbol). THRB genotype is given below relevant symbols (M = mutant; WT = wild-
pD-1+ T cells prompt pulmonary fibrosis TSHoma. Neither consented to surgery and both were treated type allele). Shaded symbols indicate mutation carrier. Hatched symbol indicates an
Although immunological T cells expressing programmed to induce fibroblasts to produce collagen in vitro. Blocking with somatostatin analog. In the eight remaining probands, eight obligate heterozygote who died a few years before this study was initiated
cell death 1 (PD-1) are sometimes described as exhausted, PD-1 in the co-culture system prevented this induction and different THRB mutations were identified, seven previously A
they are not too exhausted to wreak havoc in a variety of associated cytokine production from the T cells. Furthermore, reported and one novel (p.His435Arg) [Table 1]. Two of the β2
settings. Celada and colleagues examined cells from patients blocking PD-1 in a mouse model of pulmonary fibrosis mutations were de-novo (p.Leu328Ser and p.Pro453Ser). The β1 DNA Binding Hinge T 3 -binding
with sarcoidosis or idiopathic pulmonary fibrosis and saw an reduced fibrosis symptoms. remaining six were autosomal dominantly inherited. All muta- Exons 4–6 Exons 7–8 Exon 9 Exon 10
increase in PD-1 + CD4 + T cells relative to healthy controls. Sci Transl Med 2018; 10: eaar8356 tions were located within the previously described mutation Mutation cluster 3 2 1
These cells were mostly T helper 17 cells and were able Eitan Israeli clusters 1 and 2 [Figure 1A] [1]. These eight families came from 328 438
7
diverse ethnic backgrounds and included two Arab Muslim 8 4 5 2 435 6 1 3
families and six Jewish families. The latter were from several 320 338 453
Capsule different ethnic groups: Ashkenazi (2 families), Moroccan (1),
Georgian (1), and diverse ethnic combinations (2). B
waking up in a trap I
1 2 1 2
Cancer patients who have undergone successful treatment the accompanying formation of neutrophil extracellular traps nOVEl THRB gEnE MISSEnSE MuTATIOn (p.HIS435ARg)
3
1
can experience a relapse of their disease years, or even (NETs) could convert dormant cancer cells to aggressive lung The proband of family 7, a 30 year old Arab Muslim woman, II x3 Wt/Wt 2 Wt/Wt
decades, later. This is because cancer cells that have metastases. Awakening of these cells was associated with was referred after 5 years of follow-up with repeated TFTs
disseminated beyond the primary tumor site enter a state of NET-mediated remodeling of the extracellular matrix and showing persistent elevation of serum FT4 and FT3 levels III 1 2 3 4
dormancy, where they remain viable but and not proliferating. could be prevented by an antibody against the remodeled along with non-suppressed TSH (data not shown). At the time x2 x3 Wt/Wt M/Wt x4 M/Wt Wt/Wt x4 x4
5
Eventually, by mechanisms that are poorly understood, these version of a matrix protein called laminin-111. of evaluation, the patient had a goiter and sinus tachycardia, IV 1 2 3 4 5 Wt/Wt
partially controlled by propranolol (160 mg/day).
clinically undetectable cells “wake up” and form actively
PERFECTOR growing metastases. Studying mouse models, Albrengues Science 2018; 361: eaao4227 which predicted in an amino acid substitution (histidine to M/Wt Wt/Wt Wt/Wt M/Wt Wt/Wt Wt/Wt M/Wt M/Wt M/Wt
Sanger sequencing identified a single nucleotide change,
8
9
6
7
and co-authors found that sustained lung inflammation and
Eitan Israeli
arginine) in codon 435, (p.His435Arg). This change was not
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