. 2023 Mar 2;110(3):499-515.

doi: 10.1016/j.ajhg.2023.01.006. Epub 2023 Jan 31.

Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Margaux Serey-Gaut¹, Marisol Cortes², Periklis Makrythanasis³, Mohnish Suri⁴, Alexander M R Taylor⁵, Jennifer A Sullivan⁶, Ayat N Asleh², Jaba Mitra⁷, Mohamad A Dar², Amy McNamara², Vandana Shashi⁶, Sarah Dugan⁸, Xiaofei Song⁹, Jill A Rosenfeld¹⁰, Christelle Cabrol¹¹, Justyna Iwaszkiewicz¹², Vincent Zoete¹³, Davut Pehlivan¹⁴, Zeynep Coban Akdemir¹⁵, Elizabeth R Roeder¹⁶, Rebecca Okashah Littlejohn¹⁶, Harpreet K Dibra⁵, Philip J Byrd⁵, Grant S Stewart⁵, Bilgen B Geckinli¹⁷, Jennifer Posey¹⁸, Rachel Westman⁸, Chelsy Jungbluth⁸, Jacqueline Eason⁴, Rani Sachdev¹⁹, Carey-Anne Evans²⁰, Gabrielle Lemire²¹, Grace E VanNoy²², Anne O'Donnell-Luria²¹, Frédéric Tran Mau-Them²³, Aurélien Juven²³, Juliette Piard¹¹, Cheng Yee Nixon²⁰, Ying Zhu²⁴, Taekjip Ha⁷, Michael F Buckley²⁴, Christel Thauvin²⁵, George K Essien Umanah², Lionel Van Maldergem²⁶, James R Lupski²⁷, Tony Roscioli²⁸, Valina L Dawson²⁹, Ted M Dawson³⁰, Stylianos E Antonarakis³¹

Affiliations

¹ Centre de génétique humaine, Université de Franche-Comté, Besançon, France. Electronic address: sereymargaux@gmail.com.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
⁴ Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁶ Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
⁷ Department of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
⁸ Providence Medical Group Genetic Clinics, Spokane, WA, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
¹² Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
¹³ Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Computer-Aided Molecular Engineering, Department of Oncology, Ludwig Institute for Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland.
¹⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; University Texas Health Science Center, Houston, TX 77030, USA.
¹⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Medical Genetics, Marmara University School of Medicine, Istanbul 34722, Turkey.
¹⁸ Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
²⁰ Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia.
²¹ Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
²² Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
²³ UF6254 Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
²⁴ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
²⁵ INSERM UMR1231 GAD, Bourgogne Franche-Comté University, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Dijon-Burgundy University Hospital, Dijon, France.
²⁶ Centre de génétique humaine, Université de Franche-Comté, Besançon, France; Clinical Investigation Center 1431, National Institute of Health and Medical Research (INSERM), CHU, Besancon, France; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France.
²⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
²⁸ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
²⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Medigenome, Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland. Electronic address: stylianos.antonarakis@unige.ch.

PMID: 36724785
PMCID: PMC10027477
DOI: 10.1016/j.ajhg.2023.01.006

Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Margaux Serey-Gaut et al. Am J Hum Genet. 2023.

. 2023 Mar 2;110(3):499-515.

doi: 10.1016/j.ajhg.2023.01.006. Epub 2023 Jan 31.

Authors

Affiliations

¹ Centre de génétique humaine, Université de Franche-Comté, Besançon, France. Electronic address: sereymargaux@gmail.com.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
⁴ Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁶ Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
⁷ Department of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
⁸ Providence Medical Group Genetic Clinics, Spokane, WA, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
¹² Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
¹³ Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Computer-Aided Molecular Engineering, Department of Oncology, Ludwig Institute for Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland.
¹⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; University Texas Health Science Center, Houston, TX 77030, USA.
¹⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Medical Genetics, Marmara University School of Medicine, Istanbul 34722, Turkey.
¹⁸ Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
²⁰ Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia.
²¹ Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
²² Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
²³ UF6254 Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
²⁴ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
²⁵ INSERM UMR1231 GAD, Bourgogne Franche-Comté University, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Dijon-Burgundy University Hospital, Dijon, France.
²⁶ Centre de génétique humaine, Université de Franche-Comté, Besançon, France; Clinical Investigation Center 1431, National Institute of Health and Medical Research (INSERM), CHU, Besancon, France; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France.
²⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
²⁸ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
²⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Medigenome, Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland. Electronic address: stylianos.antonarakis@unige.ch.

PMID: 36724785
PMCID: PMC10027477
DOI: 10.1016/j.ajhg.2023.01.006

Abstract

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.

Keywords: TTI1 gene; autosomal recessive; consanguinity; gene; mendelian disorders; microcephaly; neurodevelopment; pathogenic variants.

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Conflict of interest statement

Declaration of interests S.E.A. is a co-founder and CEO of Medigenome, Swiss Institute of Genomic Medicine, and serves in the Scientific Advisory Board of the “Imagine” Institute in Paris. The Department of Medical and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. J.R.L. has stock ownership in 23andMe; is a paid consultant for Regeneron Genetics Center; and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting, and serves on the Scientific Advisory Board of Baylor Genomics.

Figures

**Figure 1**
Pedigrees and clinical photographs of the affected individuals (A) Pedigrees of the 11 affected individuals with bi-allelic, likely pathogenic *TTI1* variants. (B) Clinical photographs of selected affected individuals. Individuals 1 (F1.IV-2) and 2 (F1.IV-3): smooth philtrum, thin upper lip. Individual 4 (F3.II-2): fine facial features with round face, low-set ears, and widely spaced teeth. Individual 5 (F4.II-3): lateral flare of eyebrows, upturned nose, wide mouth with fully everted lower lip, and large protruding ears with underfolded helices. Individual 6 (F5.III-5): narrow forehead, strabismus, upslanting palpebral fissures, blue sclerae, prominent nose, micrognathia, and short philtrum. Individual 7 (F5.III-6): narrow forehead, upslanting palpebral fissures, epicanthus, blue sclerae, prominent nose, micrognathia, and short philtrum. Individual 10 (F8.II-2): prominent metopic suture, upslanting palpebral fissures, infraorbital creases, and anteverted nares.

**Figure 2**
Protein levels of *TTI1* variants in HEK293T cells (A) Immunoblot images of TTI1-Flag accumulation in HEK293T. Control cells were transfected with empty plasmid vector. (B) Quantification of band intensity of anti-FLAG blot normalized to anti-Actin blots in (A) (n = 4). (C) Quantification of band intensity of anti-TTI1 blot normalized to anti-Actin blots in (A) (n = 4).

**Figure 3**
*TTI1* variants alter mTOR complex 1 (mTORC1) composition (A) Schematic depiction of mTORC1-TTI1-Flag SiMPull. (B) Representative quartz slide images from SiMPull shown in (A) with the TTI1 variants. Control is similar experiments with cells without TTI1-Flag. (C and D) Graphical representation of relative amount of mTOR (C) or of Raptor (D) bound to TTI1-Flag (n = 4 for each). (E) Graphical representation of relative amount of mTORC1 (mTOR-Raptor) bound to TTI1-Flag (n = 4). (F) Schematic depiction of different mTOR oligomeric states and graphical representation showing the distribution of the different mTOR complexes in the presence of the TTI1 variants (n = 4). (G) Schematic depiction of different mTORC1 composition (mTOR, mT-Raptor,R) complexes and graphical representation showing the distribution of the different Raptor-mTOR complexes in the presence of the *TTI1* variants (n = 4). Data in (C)–(G) are mean ± SEM experiments, ^∗p < 0.05; n.s., p > 0.05, ANOVA with Tukey-Kramer post-hoc test compared with wild-type.

**Figure 4**
*TTI1* variants alter mTORC1 activation by amino acids (A) Representative immunoblots of showing mTORC1 activation (phosphorylation) status during normal amino acids fed (+), starvation (−), and starvation followed by amino acid supplementation (−/+). (B) Quantification of phosphorylated mTOR (phos-mTOR, S2448) normalized to total mTOR (mTOR) of images in (A) (n = 3). (C) Quantification of phosphorylated S6K (phos-S6K, T389) normalized to total S6K (S6K) of images in (A) (n = 3). (D) Quantification of phosphorylated 4EBP1 (phos-4EBP1) normalized to total 4EBP1 (4EBP1) of images in (A) (n = 3). (E) Quantification of phosphorylated PRAS40 (phos-PRAS40) normalized to total PRAS40 (PRAS40) of images in (A) (n = 3). QA (F) Representative immunoblots of showing mTORC1 activation (phosphorylation) status in the absence (− −) or presence (+ −) of MHY1485 or Rapamycin (− +). (G) Quantification of phosphorylated S6K (phos-S6K, T389) normalized to total S6K (S6K) of images in (F) (n = 3). Data in (B)–(E), (G), and (H) are mean ± SEM of experiments performed, ^∗∗∗p < 0.001, ^∗∗p < 0.01, ^∗p < 0.05, n.s., p > 0.05, ANOVA with Tukey-Kramer post-hoc test compared with WT.

**Figure 5**
*TTI1* likely pathogenic variants affect cell cycle progression (A) Representative images of starved cells co-expressing TTI1-flag (wild-type or variant, purple), CDK2 sensor-GFP (green), and H2B-RFP (red). (B) Representative images of re-fed starved cells to stimulate cell cycle progression. (C) Schematic of CDK2 activity and colocalization with H2B at different phases of the cell cycle. (D and E) Graphical representative of the percentage of the different phases of the cell cycle in starved cells (D) and re-fed cells (E) of images in (A) and (B) (n = 4). Data in (D) and (E) are mean ± SEM of experiments performed, ^∗p < 0.05, n.s., p > 0.05, ANOVA with Tukey-Kramer post-hoc test compared with WT.

**Figure 6**
mTORC1 activation altered in cells from affected individuals (A) Representative immunoblots showing mTORC1 activation (phosphorylation) status during normal amino acids fed (+), starvation (−), and starvation followed by amino acid supplementation (−/+). (B and C) Quantification of phosphorylated S6K (phos-S6K, T389) and 4EBP1 (phos-4EBP1) normalized to total proteins of images in (A) (n = 3). (D–G) Graphical representative of basal and amino acids stimulated mTORC1 activation. (H) Representative immunoblots showing mTORC1 activation (phosphorylation) status in the absence (− −) or presence of MHY1485 (+ −) or Rapamycin (− +). (I and J) Quantification of phosphorylated mTOR and S6K normalized to total proteins of images in (F) (n = 3). Data in (B)–(G), (I), and (J) are mean ± SEM of experiments performed, ^∗p < 0.05, n.s., p > 0.05, ANOVA with Tukey-Kramer post-hoc test compared with control.

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Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Affiliations

Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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Grants and funding

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