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, Gly275Asp) inherited from unrelated parents was reported, 2016.
, Patient 1 (Figure 1A) underwent multiple genetic testing and no candidate variant was detected 100 by targeted-sequencing. By whole-exome sequencing (WES) we identified only one de novo 101 loss-of-function nonsense variant in the PSPN gene
, This variant, coding for a 10 amino acid truncated protein, was considered to be non-pathogenic 103 as PSPN is largely tolerant to loss-of-function (LoF) variants (probability of LoF intolerance, homozygous variants, p.100
, He presents facial 121 dysmorphism (tall forehead, short palpebral fissures, long noise, retrognathia) consistent with 122 the other BBSI patients previously reported. Genetic and molecular investigations performed 123 in Patient 2 (Figure 1B) include high-resolution karyotype, SNP microarray, plasma amino 124 acids, urine organic acids, and urine amino acids. All of these studies were normal with the 125 exception of urine organic acids and plasma amino acids, which were abnormal in non1.92kg, 43.5cm length, and OFC of 33.3cm. Prenatal concerns included 129 ventriculomegaly and dichorionic-diamniotic twin gestation; her brother is healthy and 130 developmentally appropriate for his age. After birth, a cleft palate, micrognathia, choanal 131 atresia, and a congenital heart defect were noted
, Despite intensive therapies, Patient 2 cycles through periods of achievement followed by 137 regression, usually around one month following skill acquisition (for example, patient 2 stopped G tube. Dysmorphic features associated with BBIS include: 140 microcephaly, prominent forehead, short palpebral fissures with epicanthal folds, low-hanging 141 columella, abnormally shaped dentition with malocclusion. She also presents cupped ears, 142 small anteverted nares, down-turned corners of the mouth with a tented upper lip, maxillary 143 hypoplasia, prominent fetal pads on hands and feet, and bilateral overlapping toes. Patient 2 has 144 additional medical complications that include alternating exotropia, nystagmus, hyperopia
, The haplotype p.(Trp100Arg, Val234Leu, Gly275Asp) is recurrent in the European population
, the missense c.596 G>A, p.(Gly190Glu) variant identified in Patient 2 and a patient 172 reported previously, The haplotype composed of the three missense variants p.(Trp100Arg, Val234Leu, Gly275Asp) BBIS form of ID, 2016.
, Figure 1C), 2016.
, Gly275Asp alone or the truncating variant Arg87* reduce the THOC6 protein stability 176 At first, we investigated if THOC6 variants affect stability of the proteins in HEK293T cells
, HEK293T cells were transfected with plasmids expressing human FLAG-tagged wild type or 178 mutant forms with: Trp100Arg
, Trp100Arg), p.(Gly190Glu) and p.(Arg87*)
, All the THO complex subunit proteins, including THOC6 are localized in the nucleus, 187 specifically co-localizing with the splicing factors in the nuclear speckle domains, vol.188, 2005.
, We performed immunostaining on HeLa cells transfected 191 with plasmids expressing FLAG-tagged human wild-type or variant THOC6 cDNAs using anti192 FLAG antibody and found that whereas wild-type showed a normal nuclear localization, the 193 triple mutant, Gly190Asp and Arg87* THOC6 showed an abnormal cytosolic localization 194, 2013.
, NLS) was identified in THOC6, we hypothesized that its variant THOC6 expression plasmids. A Coomassie Blue staining revealed the presence, 207 among the immunoprecipitated proteins, of FLAG-THOC6 along with other proteins at an 208 estimated size of 75 and 28 KDa (data not shown), The immunopreciptated proteins were 209 immunoblotted for THOC1, THOC2, THOC3, THOC4/ALY, THOC5, CIP29 and CBP80 another BBSI affected individual, 2016.
, Thoc1 and Thoc5 knockout mice were embryonically 238 lethal, indicating their important role during development, THOC5/1, 2005.
, Arg87* lead to a 240 mislocalization of THOC6 in the cytosplasm, and to a loss or a decrease of its interactions with 241 THOC1 and THOC5. Therefore, the variants might make THOC6 unable to carry out its normal 242 function and impact mRNA export, leading to clinical outcomes. Our results combined to the 243 previous ones indicate that compound heterozygosity for the two most common pathogenic 244 missense variants (the haplotype and Gly190Glu found in Patient2) appears, on the basis of 245 single patient descriptions, as severe as homozygosity for the haplotype (Patient 1, and Patient 246 3 described by Casey et al.), homozygosity for a null mutation
, El Bounkari 257 et al. previously showed that THOC5 directly interacts with THOC7 and that this interaction is 258 responsible for bringing THOC7 to the nucleus. However, in our case, the amino acid change 259 leading to an abnormal cytoplasmic THOC6 localization, Trp100Arg, does not affect 260 interactions with THOC5 and THOC1. Therefore, disruptions of these interactions might not between THOC2 and THOC6, vol.7, 2005.
, Missense variants in THOC2 were reported in patients with an X-linked ID characterized by 269 elevated BMI, speech delay, short stature and seizures a phenotype that do not well overlap 270 with BBIS, 2015.
, which could explain that consequences are different when they are altered by genetic 276 variants. The microcephaly is significantly more pronounced in these patients than in patients 277 with THOC2 mutations, which is consistent with a role of THOC6 in apoptotic processes, THO/TREX subunits are differentially recruited to specific subsets of mRNA, 2010.
, In conclusion, we have expanded the cohort of BBIS affected individuals by reporting two 283 additional European patients, both carrying the same haplotype
, Europe and composed of three missense variants. This highlights its relative high frequency
, We demonstrated that this haplotype, as well as two other recurrent variants identified in non288 consanguineous European population, the truncating p.(Arg87*) and the missense 289 p.(Gly190Glu) variants, alter THOC6 physiological nuclear localization and its interaction with 290 other members of the THO complex
, MATERIALS AND METHODS Patient recruitment and genomic analysis Patient1 underwent multiple genetic testing that included karyotyping, array comparative 297 genomic hybridization, fragile X-test and targeted-sequencing of more than 400 genes 298 implicated in ID. As no clear pathogenic variant was detected, a trio-whole exome sequencing 299 was then performed. Libraries and captures from genomic blood DNA
, All Exon V5 Kit (Agilent Technologies), and 100 bp paired-end 301 sequencing was performed on the HiSeq2500 sequencer (Illumina). Reads were aligned and 302 variants called and annotated as described previously, 2014.
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, Site-directed mutagenesis
, The variant FLAG-THOC6 expression plasmids were generated by site-directed mutagenesis 314 of thepcDNA3.1-FLAG-THOC6 construct reported previously
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, CTGTCAGGTGGCGAGGATGaAGCTGTTCGAC-3' and c, vol.569
, The variant FLAG-THOC6 plasmids 325 326 were confirmed by sequencing
, Western Blot analysis 328 HEK293T cells were transiently transfected with the different plasmids expressing FLAG329 tagged wild-type or variant forms of THOC6 using Lipofectamine2000 (Invitrogen) and 330 harvested 36 hours after transfection. For immunoblotting analysis, proteins were lysed in RIPA 331 buffer combined with protease inhibitors (Roche), THOC6 expression was analyzed by SDS
, PAGE, and immunoblotting was performed with anti-FLAG (1:1000, F1804, SIGMA) and anti
, TUB2A2 (in house, 1:4000) antibodies. Protein semi-quantification was done by measuring the
, For immunoprecipitation studies, proteins were extracted using a NP40 buffer combined with 339 anti-proteases (Roche) (25mM Tris-HCl pH8, 150mM NaCl, 10% glycerol, p.2
, FLAG-THOC6 was immunoprecipitated with Dynabeads Protein A (Invitrogen) using 341 2?g of mouse anti-FLAG antibody (F1804, SIGMA) or 2?g of a negative control
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