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Sanger sequencing identified a single nucleotide change,
x4
x4
453
435
3
7
1
6
438
1
Exon 10
In the 10 patients included in the study, all THRB coding
Refetoff, Dumitrescu [24]
Adams et al. [22] and
Adams et al. [22]
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#131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Black
Refetoff, Dumitrescu [24]
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Adams et al. [22] and
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Adams et al. [22]
Grace et al. [23]
4. Hod N, Anconina R, Levin D, Tiktinsky E, Ezroh
Adams et al. [22]
Adams et al. [22]
3. Franzius C, Biermann M, Hülskamp G, et al.
Reference
The questionnaire was divided into two main sections. The
2. Sharma P, Mukherjee A, Karunanithi S, et al.
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Original articles Original articles 2 5 AD de-novo AD AD AD de-novo AD AD 3 338 328 2 5 9 Wt/Wt T 3 -binding Wt/Wt 8 Exon 9 4 2 320 4 8 Wt/Wt 3 1 7 2 5 4 8 symbol Inheritance Family M/Wt M/Wt 7 1 3 M/Wt 3 M/Wt 2 6 Exons 7–8 Wt/Wt x4 5 1 Hinge Wt/Wt 4 2 2 M/Wt Wt/Wt M/Wt ctttgttcttggaag… ...acagaactcttcccc-C/A- ctttgttcttggaag... ...acagaactcttcccc-C/T- cttcctgcacatgaa… ...cctgccatgccagcc-G/A- 6 A/G
here, to the best of our knowledge, only two previously pub- All three syndromes share laboratory features of inappropriate severe psychomotor retardation, dysmor- enzyme, and it was also present in normal defective endosomal intracellular protein
lished case reports described patients in Israel with genetically serum levels of THs with non-suppressed TSH, although levels phic features, and marked leukocytosis amounts. trafficking due to inherited mutations in
proven RSTH [12,13]. of the different THs differ considerably between the different (> 100,000 mm 3 ). Furthermore, he was The last piece of the puzzle was solved the VPS45 gene [19]. This gene encodes a
Sixty-two percent of affected individuals were females, syndromes. Dumitrescu and Refetoff [1] and Refetoff et al. [7] found to have a very rare blood group, when we used a functional cloning approach protein that regulates membrane traffick-
which is not significantly different from expected if both gen- and colleagues presented a comprehensive review of these Bombay, in which the H antigen is missing and were able to identify the specific GDP ing through the endosomal system. In the
ders are equally affected (P = 0.27), as previously reported [1]. various syndromes. Patients with all forms of RSTH would on the surface of red cells. This finding and fucose transporter, which moved fucose neutrophil, a protein complex containing
The ethnic background of affected families, two Arab Muslim be expected to meet our initial criteria for inclusion. Our fail- the psychomotor retardation with dysmor- from the cytoplasm into the Golgi appa- VPS45 is responsible to beta-1 integrin
and six Jewish, reflects the population make-up of the country ure to identify additional cases with RSTH syndromes other phic features were never reported in LAD. ratus, a place where fucosylation into gly- recycling between the endocytic com-
(20% Arab Muslim) and does not suggest any ethnic bias in than RTH-β supports the findings that these defects are also Furthermore, integrin (CD18) expression coproteins occurs. We found the mutation partment and the plasma membrane, a
disease prevalence. Two of the eight THRB mutations were extremely rare in the general Israeli population. was normal on the leukocyte surface. As in a region that was highly conserve during process required for cell motility. Indeed
de-novo (p.Pro453Ser, p.Leu328Ser), consistent with previous this was found only in one patient, we could evolution, which pointed to its importance VSP45 protein levels were reduced in the
reports [12]. Each of the inherited mutations was limited to a DOES THE InTROn COnTROl REgIOn VARIAnT (RS2596623) MODIfy not determine whether it was a new syn- in the transporter function [18]. patient’s cells. This information underlies a
single extended family, excluding a founder mutation in any of THE RTH-β ClInICAl pHEnOTypE? drome. Several months later, Dr. Friedman The pathological mechanisms causing new immunodeficiency syndrome involv-
these ethnic groups. Consistent with most previous reports, and Consistent with previous findings [1], the clinical presenta- from Hasharon Hospital contacted us. He the mental and growth retardation are still ing impaired neutrophil function and has
despite the fact that some Israeli populations have a high preva- tion of THRB gene mutation carriers in our cohort varied had seen a patient with the Bombay blood unclear, but answers may become more been designated as congenital neutropenia
lence of consanguinity, inheritance was autosomal dominant in considerably in patients, even among individuals within the group. When asked about the features seen clear with the use of the induced pluripo- type 5. The cellular phenotypes were res-
all multi-generational families. Recessive inheritance has been same family [Table 2]. The importance of genetic variation in his patient, he confirmed that his patient tent stem cell techniques. cued by transfecting mutant fibroblasts
reported, but is exceedingly rare and typically associated with within non-coding regulatory regions for disease causation had exactly the same abnormalities and with the wild type VPS45 gene, linking
very severe phenotypes [1]. and modulation of disease phenotype is being increasingly thus it was clear that we were dealing with a VpS45 DEfICIEnCy: COngEnITAl this gene specifically to patient symptoms.
All previously reported causal mutations are located in the recognized [16]. Alberobello et al. [3] proposed that cis-act- new syndrome, which we called Rambam– nEuTROpEnIA TypE 5 Furthermore, a zebrafish model of VPS45
THRB gene region coding for the ligand-binding domain of ing variants within a putative regulatory intron region could Hasharon syndrome [17]. We were able to PIDs illuminate basic mechanisms of deficiency, specifically created for this
the receptor, clustered into three hot spots, which are rich in explain some of this phenotypic heterogeneity. However, we show that the adhesion and the migration immune processes. One critical element of study, exhibited marked paucity of neutro-
CpG nucleotides and thus prone to single nucleotide substitu- failed to identify any suggestion of an effect of the ICR variant of the leukocytes were defective, but we this system, the neutrophil, plays a particu- phils, mimicking patient phenotype.
tions [1]. In our study, all of the mutations, including the novel that we evaluated on disease phenotype. Thus, although our did not understand the causative molecu- larly prominent role in the defense against
mutation (p.His435Arg), were located within two of these three double heterozygotes sample size is too small to draw defini- lar defect. At that time the various steps of bacterial and fungal infections. Congenital STIM1 DEfICIEnCy
clusters [Figure 1A]. tive conclusions, our findings do not support the hypothesis the adhesion cascade were still unknown. neutrophil defects can involve certain steps Rechavi identified a new PID syndrome
We identified one novel mutation (p.His435Arg) in an Arab of Alberobello and colleagues. In 1990, the ligand for the selectins, sialyl- throughout the development, maturation, associated with autoimmune phenomena
Muslim family. Although functional studies were not per- Lewis X, was discovered by Paulson. As and function of the neutrophils, includ- and muscular hypotonia. The molecular
formed, it is highly likely that this mutation was causal, since pREgnAnCy AnD RESISTAnCE TO THyROID HORMOnE SynDROME we thought that this could be defective in ing endocytosis. Primary endosomal characterization of the patients led to the
three different mutations in the same codon have been previ- We determined the incidence of pregnancy and post-natal our syndrome, we asked Paulson for the defects, which are responsible for severe identification of a novel mechanism for PID
ously reported in RTH-β patients [9,10,14] and the mutation co- complications when the mother, the fetus, or both carry a monoclonal antibody against the ligand. immunodeficiency without associated resulting from mutations in stromal inter-
segregated perfectly with diagnostic clinical findings in this large THRB mutation. We did not observe increased miscarriage We found that the sialyl-Lewis X (CD15) dysmorphism, were first described in 2013 action molecule 1 (STIM1) in the endoplas-
family [Table 2, Figure 1B]. While the precise mechanism by rates in any of the groups. Our observed miscarriage rate was almost completely absent on the sur- when Prof. Raz Somech and his group mic reticulum that activates ORAI1-CRAC
which this specific mutation causes receptor dysfunction is not in mutation-carrying mothers (16%) is like that recently face of our patient’s leukocytes. at Sheba Medical Center, together with channels, thus crippling calcium entry to T
known, codon 435 is located in the gene region coding for the reported in the United States national pregnancy analysis As both the H antigen and CD15 incor- collaborators from the United States and cells and muscle cells resulting in a complex
ligand-binding domain of the receptor where virtually all THRB series [17]. The somewhat greater rate observed in the unaf- porate fucose into their protein complex, Germany, investigated five children from clinical phenotype [20].
mutations described so far are located. Mutations in this region fected mothers (36%) is probably skewed due to the small we postulated a general defect in fucose a Palestinian family who presented with PID may provide useful insights and
have been reported to cause either reduced affinity or abnormal numbers (n=4) and the relatively high miscarriage rate in two metabolism as the primary defect [16]. poor weight gain, hepatosplenomegaly, and complement experimental approaches
interaction with one or more cofactors involved in TH action of the unaffected mothers. After conducting some in vitro and in vivo severe infection with deep seated abscesses. to the study of the endosome function in
[1]. More specifically, Hassan and co-authors [15] reported that Affected mothers appeared to have an increased incidence studies, we showed that the adhesion defect All of the children had severe neutropenia health and diseases.
codon 435 is particularly critical for receptor function since it of gestational hypertension and poor weight gain during preg- was solely due to the inability of the leuko- with less than 200 neutrophils per mm 3 .
creates an essential functional component of the protein referred nancy. Only those pregnancies in which both the mother and cyte to bind to selectin and has nothing to Their adaptive immunity (T and B cell)
to as the His-Phe switch. Mutations that disrupt this specific fetus carried the THRB mutation appeared to be associated do with the integrins. Thus, we called this was found to be normal. The first genetic Acknowledgement
I would like to thank Prof. Shiloh, Prof.
codon severely inhibit T3-mediated activation of the receptor. with an increased incidence of SGA at birth and poor postnatal new LAD, LAD II, and the one connected analysis did not revealed any mutation in Rechavi, and Prof. Somech for their help in
Although most common, THRB mutations are not the only weight gain. Our data imply that this impact on birth weight to the integrin defect was referred to as all of the genes known to be associated preparing this manuscript
cause of reduced sensitivity to thyroid hormone. THR alpha may be clinically important since SGA in this sub-group was LAD I [18]. with neutropenia and thus the researchers
(THRA) mutations have been reported but are far more rare, relatively severe (< 5th percentile for Israel’s newborn popula- We then studied the primary defect in performed homozygosity mapping using
with only a few cases to date reported since 2011. Also described tion [8]). fucose metabolism and found a marked single-nucleotide polymorphism arrays. Correspondence
Dr. A. Etzioni
are TH cell membrane transporter (MCT8) defects. One Israeli These findings were unexpected, since mutation mismatch decreased in the activity of GDP-d- This procedure was followed by whole Ruth Children’s Hospital, Rambam Healthcare
patient has been described with a deletion in this gene [13]. between the mother and fetus was predicted to cause relative mannose-4,6 hydratase, an enzyme essen- exome sequencing, and homozygous muta- Campus, Haifa 31096, Israel
Impaired intracellular 5’-deiodination of T4 to T3 has also hypothyroidism in affected fetus of a normal mother and rela- tial for fucose production. However, no tion was found in the VPS45 gene. In the phone: (972-4) 777-4411
fax: (972-4) 777-4499
been described, although these appear to be exceedingly rare. tive hyperthyroidism in a normal fetus of an affected mother. mutation was found in the cDNA of the original article, the researchers described a email: etzioni@rambam.health.gov.il

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