Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome

E. Stellacci, K. Steindl, P. Joset, L. Mercurio, M. Anselmi, S. Cecchetti, L. Gogoll, M. Zweier, A. Hackenberg, G. Bocchinfuso, L. Stella, M. Tartaglia, A. Rauch

Research output: Contribution to journalArticle

Abstract

Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function. © 2018 Wiley Periodicals, Inc.
Original languageEnglish
Pages (from-to)959-964
Number of pages6
JournalHuman Mutation
Volume39
Issue number7
DOIs
Publication statusPublished - 2018

Fingerprint

Zinc Fingers
Mutation
Megalencephaly
Amino Acid Substitution
Protein C
Intellectual Disability
Insulin
Glucose
Muscles
Primrose syndrome

Keywords

  • 3q13.31 microdeletion syndrome
  • functional analyses
  • mutation spectrum
  • Primrose syndrome
  • ZBTB20
  • glucose
  • glutamine
  • zinc finger protein
  • amino acid substitution
  • Article
  • autism
  • case report
  • child
  • chromosome deletion
  • clinical article
  • clinical feature
  • diabetes mellitus
  • female
  • gene
  • gene deletion
  • gene mapping
  • gene mutation
  • genetic disorder
  • genomics
  • glucose metabolism
  • human
  • insulin resistance
  • intellectual impairment
  • macrocephaly
  • male
  • missense mutation
  • muscle atrophy
  • preschool child
  • priority journal
  • rare disease
  • school child
  • tall stature
  • whole exome sequencing
  • wild type
  • ZBTB20 gene
  • zinc finger motif

Cite this

Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome. / Stellacci, E.; Steindl, K.; Joset, P.; Mercurio, L.; Anselmi, M.; Cecchetti, S.; Gogoll, L.; Zweier, M.; Hackenberg, A.; Bocchinfuso, G.; Stella, L.; Tartaglia, M.; Rauch, A.

In: Human Mutation, Vol. 39, No. 7, 2018, p. 959-964.

Research output: Contribution to journalArticle

Stellacci, E, Steindl, K, Joset, P, Mercurio, L, Anselmi, M, Cecchetti, S, Gogoll, L, Zweier, M, Hackenberg, A, Bocchinfuso, G, Stella, L, Tartaglia, M & Rauch, A 2018, 'Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome', Human Mutation, vol. 39, no. 7, pp. 959-964. https://doi.org/10.1002/humu.23546
Stellacci, E. ; Steindl, K. ; Joset, P. ; Mercurio, L. ; Anselmi, M. ; Cecchetti, S. ; Gogoll, L. ; Zweier, M. ; Hackenberg, A. ; Bocchinfuso, G. ; Stella, L. ; Tartaglia, M. ; Rauch, A. / Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome. In: Human Mutation. 2018 ; Vol. 39, No. 7. pp. 959-964.
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abstract = "Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function. {\circledC} 2018 Wiley Periodicals, Inc.",
keywords = "3q13.31 microdeletion syndrome, functional analyses, mutation spectrum, Primrose syndrome, ZBTB20, glucose, glutamine, zinc finger protein, amino acid substitution, Article, autism, case report, child, chromosome deletion, clinical article, clinical feature, diabetes mellitus, female, gene, gene deletion, gene mapping, gene mutation, genetic disorder, genomics, glucose metabolism, human, insulin resistance, intellectual impairment, macrocephaly, male, missense mutation, muscle atrophy, preschool child, priority journal, rare disease, school child, tall stature, whole exome sequencing, wild type, ZBTB20 gene, zinc finger motif",
author = "E. Stellacci and K. Steindl and P. Joset and L. Mercurio and M. Anselmi and S. Cecchetti and L. Gogoll and M. Zweier and A. Hackenberg and G. Bocchinfuso and L. Stella and M. Tartaglia and A. Rauch",
note = "Cited By :1 Export Date: 11 April 2019 CODEN: HUMUE Correspondence Address: Stellacci, E.; Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanit{\`a}Italy; email: emilia.stellacci@iss.it Chemicals/CAS: glucose, 50-99-7, 84778-64-3; glutamine, 56-85-9, 6899-04-3 Funding text 1: Contract Grant Sponsors: University of Zurich (University of Zurich clinical research priority program radiz); Fondazione Bambino Ges{\`u} (Vite coraggiose); Umberto Veronesi Post-doc fellowship. References: Battisti, C., Dotti, M.T., Cerase, A., Rufa, A., Sicurelli, F., Scarpini, C., Federico, A., The Primrose syndrome with progressive neurological involvement and cerebral calcification (2002) Journal of Neurology, 249, pp. 1466-1468; Carvalho, D.R., Speck-Martins, C.E., Additional features of unique Primrose syndrome phenotype (2011) American Journal of Medical Genetics, 155A, pp. 1379-1383; Collacott, R.A., O'Malley, B.P., Young, I.D., The syndrome of mental handicap, cataracts, muscle wasting and skeletal abnormalities: Report of a second case (1986) Journal of Mental Deficiency Research, 30, pp. 301-308; Cordeddu, V., Redeker, B., Stellacci, E., Jongejan, A., Fragale, A., Bradley, T.E., Hennekam, R.C., Mutations in ZBTB20 cause Primrose syndrome (2014) Nature Genetics, 46 (8), pp. 815-817; Dalal, P., Leslie, N.D., Lindor, N.M., Gilbert, D.L., Espay, A.J., Motor tics, stereotypies, and self-flagellation in primrose syndrome (2010) Neurology, 75 (3), pp. 284-286; Herv{\'e}, B., Fauvert, D., Dard, R., Roume, J., Cognard, S., Goidin, D., Vialard, F., The emerging microduplication 3q13.31: Expanding the genotype-phenotype correlations of the reciprocal microdeletion 3q13.31 syndrome (2016) European Journal of Medical Genetics, 59 (9), pp. 463-469; Lindor, N.M., Hoffman, A.D., Primrose, D.A., A neuropsychiatric disorder associated with dense calcification of the external ears and distal muscle wasting: ‘Primrose syndrome’ (1996) Clinical Dysmorphology, 5, pp. 27-34; Mattioli, F., Piton, A., Gerard, B., Superti-Furga, A., Mandel, J.L., Unger, S., Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism (2016) American Journal of Medical Genetics, 170A, pp. 1626-1629; Mitchelmore, C., Kjaerulff, K.M., Pedersen, H.C., Nielsen, J.V., Rasmussen, T.E., Fisker, M.F., Jensen, N.A., Characterization of two novel nuclear BTB/POZ domain zinc finger isoforms. Association with differentiation of hippocampal neurons, cerebellar granule cells, and macroglia (2002) Journal of Biological Chemistry, 277 (9), pp. 7598-7609; Nielsen, J.V., Nielsen, F.H., Ismail, R., Noraberg, J., Jensen, N.A., Hippocampus-like corticoneurogenesis induced by two isoforms of the BTB-zinc finger gene Zbtb20 in mice (2007) Development, 134, pp. 1133-1140; Posmyk, R., Lesniewicz, R., Chorązy, M., Wołczynski, S., New case of Primrose syndrome with mild intellectual disability (2011) American Journal of Medical Genetics Part A, 155A, pp. 2838-2840; Primrose, D.A., A slowly progressive degenerative condition characterized by mental deficiency, wasting of limb musculature and bone abnormalities, including ossification of the pinnae (1982) Journal of Mental Deficiency Research, 26, pp. 101-106; Sutherland, A.P., Zhang, H., Michaud, M., Xie, Z., Patti, M.E., Grusby, M.J., Zhang, W.J., Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis (2009) Molecular and Cellular Biology, 29 (10), pp. 2804-2815; Zhang, W., Mi, J., Li, N., Sui, L., Wan, T., Zhang, J., Cao, X., Identification and characterization of DPZF, a novel human BTB/POZ zinc finger protein sharing homology to BCL6 (2001) Biochemical and Biophysical Research Communication, 282 (4), pp. 1067-1073; Zhang, Y., Xie, Z., Zhou, L., Li, L., Zhang, H., Zhou, G., Zhang, W.J., The zinc finger protein ZBTB20 regulates transcription of fructose-1,6-bisphosphatase 1 and β cell function in mice (2012) Gastroenterology, 142, pp. 1571-1580; Zhang, H., Cao, D., Zhou, L., Zhang, Y., Guo, X., Li, H., Zhang, W.J., ZBTB20 is a sequence-specific transcriptional repressor of alphafetoprotein gene (2015) Science Reports, 5, p. 11979. , https://doi.org/10.1038/srep11979",
year = "2018",
doi = "10.1002/humu.23546",
language = "English",
volume = "39",
pages = "959--964",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",
number = "7",

}

TY - JOUR

T1 - Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome

AU - Stellacci, E.

AU - Steindl, K.

AU - Joset, P.

AU - Mercurio, L.

AU - Anselmi, M.

AU - Cecchetti, S.

AU - Gogoll, L.

AU - Zweier, M.

AU - Hackenberg, A.

AU - Bocchinfuso, G.

AU - Stella, L.

AU - Tartaglia, M.

AU - Rauch, A.

N1 - Cited By :1 Export Date: 11 April 2019 CODEN: HUMUE Correspondence Address: Stellacci, E.; Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di SanitàItaly; email: emilia.stellacci@iss.it Chemicals/CAS: glucose, 50-99-7, 84778-64-3; glutamine, 56-85-9, 6899-04-3 Funding text 1: Contract Grant Sponsors: University of Zurich (University of Zurich clinical research priority program radiz); Fondazione Bambino Gesù (Vite coraggiose); Umberto Veronesi Post-doc fellowship. References: Battisti, C., Dotti, M.T., Cerase, A., Rufa, A., Sicurelli, F., Scarpini, C., Federico, A., The Primrose syndrome with progressive neurological involvement and cerebral calcification (2002) Journal of Neurology, 249, pp. 1466-1468; Carvalho, D.R., Speck-Martins, C.E., Additional features of unique Primrose syndrome phenotype (2011) American Journal of Medical Genetics, 155A, pp. 1379-1383; Collacott, R.A., O'Malley, B.P., Young, I.D., The syndrome of mental handicap, cataracts, muscle wasting and skeletal abnormalities: Report of a second case (1986) Journal of Mental Deficiency Research, 30, pp. 301-308; Cordeddu, V., Redeker, B., Stellacci, E., Jongejan, A., Fragale, A., Bradley, T.E., Hennekam, R.C., Mutations in ZBTB20 cause Primrose syndrome (2014) Nature Genetics, 46 (8), pp. 815-817; Dalal, P., Leslie, N.D., Lindor, N.M., Gilbert, D.L., Espay, A.J., Motor tics, stereotypies, and self-flagellation in primrose syndrome (2010) Neurology, 75 (3), pp. 284-286; Hervé, B., Fauvert, D., Dard, R., Roume, J., Cognard, S., Goidin, D., Vialard, F., The emerging microduplication 3q13.31: Expanding the genotype-phenotype correlations of the reciprocal microdeletion 3q13.31 syndrome (2016) European Journal of Medical Genetics, 59 (9), pp. 463-469; Lindor, N.M., Hoffman, A.D., Primrose, D.A., A neuropsychiatric disorder associated with dense calcification of the external ears and distal muscle wasting: ‘Primrose syndrome’ (1996) Clinical Dysmorphology, 5, pp. 27-34; Mattioli, F., Piton, A., Gerard, B., Superti-Furga, A., Mandel, J.L., Unger, S., Novel de novo mutations in ZBTB20 in Primrose syndrome with congenital hypothyroidism (2016) American Journal of Medical Genetics, 170A, pp. 1626-1629; Mitchelmore, C., Kjaerulff, K.M., Pedersen, H.C., Nielsen, J.V., Rasmussen, T.E., Fisker, M.F., Jensen, N.A., Characterization of two novel nuclear BTB/POZ domain zinc finger isoforms. Association with differentiation of hippocampal neurons, cerebellar granule cells, and macroglia (2002) Journal of Biological Chemistry, 277 (9), pp. 7598-7609; Nielsen, J.V., Nielsen, F.H., Ismail, R., Noraberg, J., Jensen, N.A., Hippocampus-like corticoneurogenesis induced by two isoforms of the BTB-zinc finger gene Zbtb20 in mice (2007) Development, 134, pp. 1133-1140; Posmyk, R., Lesniewicz, R., Chorązy, M., Wołczynski, S., New case of Primrose syndrome with mild intellectual disability (2011) American Journal of Medical Genetics Part A, 155A, pp. 2838-2840; Primrose, D.A., A slowly progressive degenerative condition characterized by mental deficiency, wasting of limb musculature and bone abnormalities, including ossification of the pinnae (1982) Journal of Mental Deficiency Research, 26, pp. 101-106; Sutherland, A.P., Zhang, H., Michaud, M., Xie, Z., Patti, M.E., Grusby, M.J., Zhang, W.J., Zinc finger protein Zbtb20 is essential for postnatal survival and glucose homeostasis (2009) Molecular and Cellular Biology, 29 (10), pp. 2804-2815; Zhang, W., Mi, J., Li, N., Sui, L., Wan, T., Zhang, J., Cao, X., Identification and characterization of DPZF, a novel human BTB/POZ zinc finger protein sharing homology to BCL6 (2001) Biochemical and Biophysical Research Communication, 282 (4), pp. 1067-1073; Zhang, Y., Xie, Z., Zhou, L., Li, L., Zhang, H., Zhou, G., Zhang, W.J., The zinc finger protein ZBTB20 regulates transcription of fructose-1,6-bisphosphatase 1 and β cell function in mice (2012) Gastroenterology, 142, pp. 1571-1580; Zhang, H., Cao, D., Zhou, L., Zhang, Y., Guo, X., Li, H., Zhang, W.J., ZBTB20 is a sequence-specific transcriptional repressor of alphafetoprotein gene (2015) Science Reports, 5, p. 11979. , https://doi.org/10.1038/srep11979

PY - 2018

Y1 - 2018

N2 - Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function. © 2018 Wiley Periodicals, Inc.

AB - Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function. © 2018 Wiley Periodicals, Inc.

KW - 3q13.31 microdeletion syndrome

KW - functional analyses

KW - mutation spectrum

KW - Primrose syndrome

KW - ZBTB20

KW - glucose

KW - glutamine

KW - zinc finger protein

KW - amino acid substitution

KW - Article

KW - autism

KW - case report

KW - child

KW - chromosome deletion

KW - clinical article

KW - clinical feature

KW - diabetes mellitus

KW - female

KW - gene

KW - gene deletion

KW - gene mapping

KW - gene mutation

KW - genetic disorder

KW - genomics

KW - glucose metabolism

KW - human

KW - insulin resistance

KW - intellectual impairment

KW - macrocephaly

KW - male

KW - missense mutation

KW - muscle atrophy

KW - preschool child

KW - priority journal

KW - rare disease

KW - school child

KW - tall stature

KW - whole exome sequencing

KW - wild type

KW - ZBTB20 gene

KW - zinc finger motif

U2 - 10.1002/humu.23546

DO - 10.1002/humu.23546

M3 - Article

VL - 39

SP - 959

EP - 964

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 7

ER -