TTD Patients Research Articles

Evidence of altered Redox Homeostasis in Trichothiodystrophy

Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. Although the mutations involved in this condition have been characterized, the correlation between the molecular defects and the plethora of clinical symptoms is not well understood. Recently the presence of a redox unbalance in TTD has been suggested although not clear evidences have been reported on this aspect. Therefore, in the present study, we evaluated the redox status of fibroblasts isolated from a TTD patient. In addition, to understand the ability of TTD cells to respond to oxidative insults, the cells were challenged with H2O2 and mitochondrial O2- and mitochondrial membrane potential were measured in different oxidative conditions. In addition, NRF2/BACH protein levels were also analysed in response to H2O2. The results suggested an aberrant mitochondrial response to oxidative stimuli, an increased baseline oxidative stress status in TTD and an altered NRF2/BACH level. This study emphasises that altered redox homeostasis might play a role in TTD pathogenesis and mitochondria functionality could represent an alternative therapeutic target for this condition to improve patients clinical features.

TFIIH mutations can impact on translational fidelity of the ribosome.

TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.

Debilitating hip degeneration in trichothiodystrophy: Association with ERCC2/XPD mutations, osteosclerosis, osteopenia, coxa valga, contractures, and osteonecrosis.

Trichothiodystrophy (TTD) is a rare, autosomal recessive, multisystem disorder of DNA repair and transcription with developmental delay and abnormalities in brain, eye, skin, nervous, and musculoskeletal systems. We followed a cohort of 37 patients with TTD at the National Institutes of Health (NIH) from 2001 to 2019 with a median age at last observation of 12 years (range 2-36). Some children with TTD developed rapidly debilitating hip degeneration (DHD): a distinctive pattern of hip pain, inability to walk, and avascular necrosis on imaging. Ten (27%) of the 37 patients had DHD at median age 8 years (range 5-12), followed by onset of imaging findings at median age 9 years (range 5-13). All 10 had mutations in the ERCC2/XPD gene. In 7 of the 10 affected patients, DHD rapidly became bilateral. DHD was associated with coxa valga, central osteosclerosis with peripheral osteopenia of the skeleton, and contractures/tightness of the lower limbs. Except for one patient, surgical interventions were generally not effective at preventing DHD. Four patients with DHD died at a median age of 11 years (range 9-15). TTD patients with ERCC2/XPD gene mutations have a high risk of musculoskeletal abnormalities and DHD leading to poor outcomes. Monitoring by history, physical examination, imaging, and by physical medicine and rehabilitation specialists may be warranted.

574 A deep learning classifier for the analysis of tiger tail banding in trichothiodystrophy

Trichothiodystrophy (TTD) and xeroderma pigmentosum (XP) are both rare, autosomal recessive disorders of DNA repair/ transcription genes. Despite having (different) mutations in the same genes, they have markedly different phenotypes. TTD patients have multisystem developmental abnormalities involving fetal growth, and brain, eyes, bones and immune system with normal cancer risk. XP patients have normal development and a greatly increased risk of sunlight induced skin cancer. The hallmark of TTD hair is an alternating dark and light “tiger tail” banding pattern under polarized light microscopy along with defects of the hair shaft and reduced content of sulfur containing amino acids. XP patients have normal hair. Some XP/TTD complex patients may have features of both disorders making the diagnosis and evaluation of cancer risk difficult. Here we present a U-Net convolutional neural network for segmentation and classification of tiger tail hair and normal hair images from polarized light microscopy. The model was trained with 35 TTD and 35 normal hair images. The dataset was augmented using standard crops, flips, and rotations. Shears were excluded to preserve the banded features. In future studies, a third class consisting of hair images from XP/TTD complex patients will be introduced to the U-Net to evaluate the differences in banding patterns. Use of artificial intelligence deep learning may be able to assist in diagnosis of patients with different types of hair abnormalities.

Dysregulation of LXR responsive genes contribute to ichthyosis in trichothiodystrophy

BackgroundTrichothiodystrophy (TTD) is a rare autosomal recessive disorder characterised by brittle hairs and various systemic symptoms, including photosensitivity and ichthyosis. While photosensitivity could result from DNA repair defects, other TTD clinical features might be due to deficiencies in certain molecular processes. ObjectivesThe aim of this study was to understand the pathophysiological mechanism of ichthyosis in TTD, focused on the transcriptional dysregulation. MethodsTTD mouse skin tissue and keratinocytes were pathologically and physiologically examined to identify the alteration of lipid homeostasis in TTD with ichtyosis. Gene expression of certain lipid transporter was assessed in fibroblasts derived from TTD patients and TTD mouse keratinocytes. ResultsHistopathology and electron microscopy revealed abnormal lipid composition in TTD mice skin. In addition to abnormal cholesterol dynamics, TTD mouse keratinocytes exhibit impaired expression of Liver X receptor (LXR) responsive genes, including Abca12, a key regulator of Harlequin ichthyosis, and Abcg1 that is involved in the cholesterol transport process in the epidermis. Strikingly, dysregulation of LXR responsive genes has been only observed in cells isolated from TTD patients who developed ichthyosis. ConclusionsOur results suggest that the altered expression of the LXR-responsive genes contribute to the pathophysiology of ichthyosis in TTD. These findings provide a new drug discovery target for TTD.

318 A novel pathomechanism: are Cockayne syndrome and trichothiodystrophy ribosomopathies?

The childhood premature aging diseases Cockayne syndrome(CS) and trichothiodystrophy (TTD) are attributed DNA-repair diseases as the affected genes code for DNA-repair proteins. However, no accumulating DNA-damage nor an elevated cancer incidence as a consequence of unrepaired DNA-damage has been reported in patients. The DNA-repair proteins are also involved in the key step of ribosomal biogenesis, transcription by RNA polymerase I. Here we investigated the cellular consequences of a disturbed ribosomal biogenesis and discovered that translational fidelity of the ribosomes of all patient cell lines tested is reduced. This might be due to rRNA processing defects in patient cells as detected by northern blots. Mass spectrometry analyses revealed that ribosomes from patient cells are instable when isolated under stringent conditions. The resulting reduced accuracy of the translation process produces misfolded proteins that provoke endoplasmic reticulum stress and an unfolded protein response that in turn represses transcription of RNA polymerase I and ribosomal biogenesis. This vicious circle can be disrupted by pharmaceutical chaperones offering a treatment opportunity for the affected children. Interestingly this pathomechanism, identified in CS-cells, is also active in cells of TTD patients that also suffer from retarded growth, microcephaly and premature aging. Loss of proteostasis due to an inaccurate translation has not been described in human pathology before and offers one plausible explanation for the developmental problems and premature aging characterising these children.

XPD/ERCC2 mutations interfere in cellular responses to oxidative stress.

Nucleotide excision repair (NER) is a conserved, flexible mechanism responsible for the removal of bulky, helix-distorting DNA lesions, like ultraviolet damage or cisplatin adducts, but its role in the repair of lesions generated by oxidative stress is still not clear. The helicase XPD/ERCC2, one of the two helicases of the transcription complex IIH, together with XPB, participates both in NER and in RNA pol II-driven transcription. In this work, we investigated the responses of distinct XPD-mutated cell lines to the oxidative stress generated by photoactivated methylene blue (MB) and KBrO3 treatments. The studied cells are derived from patients with XPD mutations but expressing different clinical phenotypes, including xeroderma pigmentosum (XP), XP and Cockayne syndrome (XP-D/CS) and trichothiodystrophy (TTD). We show by different approaches that all XPD-mutated cell lines tested were sensitive to oxidative stress, with those from TTD patients being the most sensitive. Host cell reactivation (HCR) assays showed that XP-D/CS and TTD cells have severely impaired repair capacity of oxidised lesions in plasmid DNA, and alkaline comet assays demonstrated the induction of significantly higher amounts of DNA strand breaks after treatment with photoactivated MB in these cells compared to wild-type cells. All XPD-mutated cells presented strong S/G2 arrest and persistent γ-H2AX staining after photoactivated MB treatment. Taken together, these results indicate that XPD participates in the repair of lesions induced by the redox process, and that XPD mutations lead to differences in the response to oxidatively induced damage.

Mutations in the TTDN1 Gene Are Associated with a Distinct Trichothiodystrophy Phenotype

Trichothiodystrophy (TTD) is a rare multisystem disorder, characterized by sulfur deficient hair with alternating dark and light “tiger tail” banding on polarized light microscopy. TTD is caused by mutations in DNA repair/transcription genes XPD, XPB or TTDA, and in TTDN1, a gene of unknown function. While most TTD patients are photosensitive, patients with TTDN1 mutations were reported to be non-photosensitive. We followed a cohort of 36 TTD patients from 2001 to 2013. We describe 5 patients from 4 families with defects in the TTDN1 gene: 4 had no photosensitivity while 1 patient exhibited cutaneous burning. Deep phenotyping of our cohort revealed differences between the patients with and without TTDN1 mutations. Delayed bone age and seizure disorders were overrepresented in the TTDN1 group (p=0.009 and p=0.024, respectively), while some characteristic TTD clinical, laboratory, and imaging findings were absent. The 3 oldest TTDN1 patients displayed autistic behaviors in contrast to the characteristic friendly, socially interactive personality in the other patients. DNA sequencing revealed deletion mutations in TTDN1 ranging in size from a single base pair to over 120kb. These data identify a distinct phenotype relationship in TTD caused by TTDN1 mutations and suggest a different mechanism of disease.

Global Contributions to the Understanding of DNA Repair and Skin Cancer

Living organisms exposed to sunlight have developed mechanisms to repair the damage that UVR induces in their DNA. These DNA repair systems are present in most life forms including bacteria, yeast, rodents, and mammals. Three rare human genetic diseases have defects in the DNA repair system called nucleotide excision repair (NER). Patients with xeroderma pigmentosum (XP) have defective NER and a more than 10,000-fold increased frequency of skin cancer, whereas patients with Cockayne syndrome (CS) or with trichothiodystrophy (TTD) have NER defects without increase in cancer. These are strikingly different clinical phenotypes (Figure 1). The dramatic differences in their manifestations reflect the complexity of DNA repair and the broad scope and central role of DNA repair on preservation of diverse biological functions. This article will review the major milestones in our understanding of DNA repair and skin cancer (Table 1). These include recognition of the clinical diseases, understanding the types of damage sunlight causes in the DNA, recognition of DNA repair in different organisms, discovery of defective DNA repair in humans, cloning of multiple human DNA repair genes, and identification of UV-type mutations in skin cancer.

A Drosophila XPD model links cell cycle coordination with neuro-development and suggests links to cancer.

XPD functions in transcription, DNA repair and in cell cycle control. Mutations in human XPD (also known as ERCC2) mainly cause three clinical phenotypes: xeroderma pigmentosum (XP), Cockayne syndrome (XP/CS) and trichothiodystrophy (TTD), and only XP patients have a high predisposition to developing cancer. Hence, we developed a fly model to obtain novel insights into the defects caused by individual hypomorphic alleles identified in human XP-D patients. This model revealed that the mutations that displayed the greatest in vivo UV sensitivity in Drosophila did not correlate with those that led to tumor formation in humans. Immunoprecipitations followed by targeted quantitative MS/MS analysis showed how different xpd mutations affected the formation or stability of different transcription factor IIH (TFIIH) subcomplexes. The XP mutants most clearly linked to high cancer risk, Xpd R683W and R601L, showed a reduced interaction with the core TFIIH and also an abnormal interaction with the Cdk-activating kinase (CAK) complex. Interestingly, these two XP alleles additionally displayed high levels of chromatin loss and free centrosomes during the rapid nuclear division phase of the Drosophila embryo. Finally, the xpd mutations showing defects in the coordination of cell cycle timing during the Drosophila embryonic divisions correlated with those human mutations that cause the neurodevelopmental abnormalities and developmental growth defects observed in XP/CS and TTD patients.

Functional and molecular genetic analyses of nine newly identified XPD‐deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes

The xeroderma pigmentosum (XP) group D protein is involved in nucleotide excision repair (NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy (TTD), XP⁄TTD complex, XP⁄Cockayne syndrome (CS) complex or the cerebro-oculo-facio-skeletal syndrome (COFS). We identified nine new XPD-deficient patients. Their fibroblasts showed reduced post-UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six patients exhibited a XP phenotype in accordance with established XP-causing mutations (c.2079G>A, p.R683Q; c.2078G>T, p.R683W; c.1833G>T, p.R601L; c.1878G>C, p.R616P; c.1878G>A, p.R616Q). One TTD patient was homozygous for the known TTD-causing mutation p.R722W (c.2195C>T). Two patients were compound heterozygous for a TTD-causing mutation (c.366G>A, p.R112H) and a novel p.D681H (c.2072G>C) amino acid exchange, but exhibited different TTD and XP/CS complex phenotypes, respectively. Interestingly, the XP/CS patient's cells exhibited a reduced but well detectable XPD protein expression compared with hardly detectable XPD expression of the TTD patient's cells. Same mutations with different clinical outcomes in NER-defective patients demonstrate the complexity of phenotype-genotype correlations, for example relating to additional genetic variations (parental consanguinity), different allelic expression due to SNPs or differences in the methylation status.

Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum

The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (P<0.001). As mutations in XPD may have differential effects on DNA repair and transcription, these observations should provide insights into the role of XPD in human pregnancy and fetal development.

Ocular Manifestations of Trichothiodystrophy

Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients. Case series. Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010; 25 had TTD and 7 had XP/TTD. Complete, age- and developmental stage-appropriate ophthalmic examination. Visual acuity (VA), best-corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, and lens assessment. Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD) that usually are exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. These TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. Although many of these can be ascribed to abnormal development--likely owing to abnormalities in basal transcription of critical genes--patients may also have a degenerative course. Proprietary or commercial disclosures may be found after the references.

High‐risk pregnancy and neonatal complications in the DNA repair and transcription disorder trichothiodystrophy: report of 27 affected pregnancies

To identify the frequency of pregnancy and neonatal complications in pregnancies carrying fetuses affected with trichothiodystrophy (TTD). We identified pregnancy and neonatal complications and serum screening results from mothers of TTD patients in a DNA repair diseases study from 2001 to 2011. Pregnancy reports of 27 TTD patients and their 23 mothers were evaluated and 81% of the pregnancies had complications: 56% had preterm delivery, 30% had preeclampsia, 19% had placental abnormalities, 11% had HELLP syndrome, and 4% had an emergency c-section for fetal distress, while 44% had two or more complications. Only 19% of the pregnancies delivered at term without complications. Eight of the ten pregnancies tested had abnormal multiple marker results including elevated levels of human chorionic gonadotrophin. Eighty-five percent of the neonates had complications: 70% were low birth weight (<2500 g), 35% had birth weight < 10 centile for gestational age, 70% had NICU admission, 67% had a collodion membrane, and 31% of the 16 males had cryptorchidism. Cataracts were present in 54% of the TTD patients examined. TTD is a multisystem disease that predisposes mothers of affected patients to substantial risks for pregnancy complications and TTD neonates have a high incidence of multiple abnormalities.

A Japanese trichothiodystrophy patient with XPD mutations

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by sulfur-deficient brittle hair complicated with ichthyosis, physical and mental retardation, and proneness to infections. Approximately half of TTD patients exhibit cutaneous photosensitivity because of the defect of nucleotide excision repair. Three genes, XPB, XPD and TTDA, have been identified as causative genes of photosensitive TTD. These three genes are components of basal transcription factor IIH. Most TTD cases have been reported in Europe and North America. We report a severely affected Japanese TTD patient with XPD mutations. Interestingly, his father has ichthyotic skin. The alteration in the paternal allele was a nucleotide substitution leading to Arg-722 to Trp (R722W), as previously reported in TTD patients. The other alteration in the maternal allele was a novel 3-bp deletion at nucleotides 67-69, resulting in the deletion of Ser-23, which is located upstream of helicase motif I and is the closest to the N-terminal end of XPD in reported mutations. The expression study showed that the two alterations were causative mutations for TTD. In Asia, it is likely that there are TTD patients who have not been diagnosed.

The XPD subunit of TFIIH is required for transcription-associated but not DNA double-strand break-induced recombination in mammalian cells

Mutations in the XPD gene can give rise to three phenotypically distinct disorders: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) or combined XP and Cockayne syndrome (CS) (XP/CS). The role of Xeroderma Pigmentosum group D protein (XPD) in nucleotide excision repair explains the increased risk of skin cancer in XP patients but not all the clinical phenotypes found in XP/CS or TTD patients. Here, we describe that the XPD-defective UV5 cell line is impaired in transcription-associated recombination (TAR), which can be reverted by the introduction of the wild-type XPD gene expressed from a vector. UV5 cells are defective in TAR, despite having intact transcription and homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Interestingly, we find reduced spontaneous HR in XPD-defective cells, suggesting that transcription underlies a portion of spontaneous HR events. We also report that transcription-coupled repair (TCR)-defective cells, mutated in the Cockayne syndrome B (CSB) protein, have a defect in TAR, but not in DSB-induced HR. However, the TAR defect may be associated with a general transcription defect in CSB-deficient cells. In conclusion, we show a novel role for the XPD protein in TAR, linking TAR with TCR.

Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair and also associated with various systemic symptoms. Approximately half of TTD patients exhibit photosensitivity, resulting from the defect in the nucleotide excision repair. Photosensitive TTD is due to mutations in three genes encoding XPB, XPD and p8/TTDA subunits of the DNA repair/transcription factor TFIIH. Mutations in these subunits disturb either the catalytic and/or the regulatory activity of the two XPB, XPD helicase/ATPases and consequently are defective in both, DNA repair and transcription. Moreover, mutations in any of these three TFIIH subunits also disturb the overall architecture of the TFIIH complex and its ability to transactivate certain nuclear receptor-responsive genes, explaining in part, some of the TTD phenotypes.

Biology of cancer and ageing

The ageing process is characterised by an increasing risk of death with advancing age. Ageing is thought to be caused by molecular damage that accumulates over the lifetime of an individual. Numerous agents can lead to persistent damage, including reactive oxygen species (ROS), which are produced as byproducts of cellular metabolism. Persistent damage will interfere with the functionality of different macromolecules and disrupt the integrity of cells, tissues and the organism. To deal with the many different types of macromolecular damage, several dedicated systems for maintenance and repair have evolved. The biological significance of these many DNA repair mechanisms is highlighted by their evolutionarily conservation and by the phenotypes of patients with inherited defects in DNA repair genes. Strikingly, defects in DNA repair mechanisms can be associated with very different clinical phenotypes, including cancer and (premature) ageing [1]. Xeroderma pigmentosum (XP) is an example of a human cancer prone syndrome that is associated with inborn defects in global genome nucleotide excision repair (GG-NER) [2]. Due to the defects in GG-NER, XP patients and corresponding mouse models show an accumulation of mutagenic lesions [3]. Mutagenic lesions may cause small point mutations if not properly repaired and their persistence will put cells at a higher risk of neoplastic transformation [4], which may explain the over 1000-fold increased risk of developing UV induced skin cancer observed in XP patients. Cockayne syndrome (CS) and Trichothiodystrophy (TTD) are two examples of human accelerated ageing syndromes that are associated with inborn defects in transcription coupled repair (TCR). Due to the defects in TCR, CS and TTD patients and corresponding mouse models show an accumulation of cytotoxic lesions in actively transcribed genes [3]. The persistence of cytotoxic lesions will lead to the induction of apoptosis and/or senescence. An excessive induction of apoptosis and/or senescence may explain for the absence of cancer as well as the presence of the segmented accelerated ageing phenotypes observed in CS and TTD patients and corresponding mouse models [5,6]. Is it likely that these same mechanisms also play a role in the pathologies and degenerative diseases commonly observed in humans at advanced ages? DNA damage does accumulate with age and will include, besides mutagenic lesions, cytotoxic lesions that will interfere with primary DNA metabolism, making cells more prone to trigger apoptosis and/or senescence [4]. Moreover, emerging data raise the possibility that cells from elderly individuals may respond differently to damage than cells from younger subjects. In mouse cells derived from tissues from young and old mice exposed to high doses of ionising irradiation (IR), an age-related decline was observed in the apoptotic response [7]. A similar reduction in mean apoptotic response with age has also been observed for human cells [8]. It has also been found that the number of senescent cells accumulates with age and that senescent cells are present at sites of age-related pathologies [9–11]. The accumulation of senescent cells in aged tissues may involve different mechanisms, including enhanced induction through the accumulation of damage, an alteration in damage response mechanisms, as well as functional changes induced by the senescence programme itself, such as resistance to apoptosis [12,13]. Upon induction of cellular senescence, a cell undergoes many morphological changes as well as several functional changes, such as the accumulation of senescence associated beta-galactosidase activity [14]. Although most of the changes induced upon senescence are beneficial, in the long run, some of these changes can also have a negative impact on tissue function and integrity, especially if senescent cells accumulate to sufficiently high numbers. Senescent cells adopt a secretory phenotype, with enhanced expression of pro-inflammatory cytokines and receptors that enhance immune surveillance by potentiating natural killer (NK) cell function. Moreover, senescence can be induced by hypermitogenic signalling, which blocks cell cycle progression, but not cell growth [15] and which may cause senescent cells to become growth

New clinico‐genetic classification of trichothiodystrophy

Trichothiodystrophy (TTD) is a congenital hair dysplasia with autosomal recessive transmission. Cross banding pattern under polarized light plus trichoschisis and a low sulfur content of hair shafts define the disorder, which is associated with variable and neuroectodermal symptoms. So-called photosensitive forms of TTD (with low level of in vitro UV-induced DNA repair, not constantly associated with marked clinical photosensitivity) are caused by mutations in genes encoding subunits of the transcription/repair factor IIH (TFIIH). Ten percentage of nonphotosensitive patients are known to have TTDN1 mutations, the specific role of which is unknown. We studied nine patients recruited at our institution and reviewed 79 with molecular analysis out of 122 TTD patients reported in literature with the aim to collect systematically the clinical findings in TTD patients and establish genotype-phenotype correlations. The frequency of congenital ichthyosis, collodion-baby type, was significantly higher in the TFIIH mutated group. Hypogonadism was significantly more frequent in the non-photosensitive group. There was no statistical difference regarding osseous anomalies. Mutations in TFIIH sub-units leading to abnormal expression in genes involved in epidermal differentiation could explain the particular dermatological changes seen in photosensitive cases of TTD. We suggest a new clinico-genetic classification of TTD, which may help clinicians confused by the current acronyms used (IBIDS, PIBIDS...). Understanding the TTD ichthyotic phenotype could lead to therapeutic advances in the management of TTD and other types of ichthyoses.

P8/TTDA Overexpression Enhances UV-Irradiation Resistance and Suppresses TFIIH Mutations in a Drosophila Trichothiodystrophy Model

Mutations in certain subunits of the DNA repair/transcription factor complex TFIIH are linked to the human syndromes xeroderma pigmentosum (XP), Cockayne's syndrome (CS), and trichothiodystrophy (TTD). One of these subunits, p8/TTDA, interacts with p52 and XPD and is important in maintaining TFIIH stability. Drosophila mutants in the p52 (Dmp52) subunit exhibit phenotypic defects similar to those observed in TTD patients with defects in p8/TTDA and XPD, including reduced levels of TFIIH. Here, we demonstrate that several Dmp52 phenotypes, including lethality, developmental defects, and sterility, can be suppressed by p8/TTDA overexpression. TFIIH levels were also recovered in rescued flies. In addition, p8/TTDA overexpression suppressed a lethal allele of the Drosophila XPB homolog. Furthermore, transgenic flies overexpressing p8/TTDA were more resistant to UV irradiation than were wild-type flies, apparently because of enhanced efficiency of cyclobutane-pyrimidine-dimers and 6–4 pyrimidine-pyrimidone photoproducts repair. This study is the first using an intact higher-animal model to show that one subunit mutant can trans-complement another subunit in a multi-subunit complex linked to human diseases.