CDK4 Loss of Function Mutations Cause Microcephaly and Short Stature

Aitana  Verdu Schlie; Maria Izabel  Arismendi; Andrea Leitch; Colin Stok; Andrea Castro  leal; David A. Parry; Antonio Marcondes Lerário; Margaret Haley; Bruna  Lucheze; Paula L Carroll; Kamila Musialik; Julia Auer; Carol-Anne Martin; Lukas Gerasimavicius; Alan J Quigley; Joya Emilie de Menezes  Correia-Deur; Joseph A Marsh; Martin A M  Reijns; Anne K Lampe; Andrew P Jackson; Alexander A. L.  Jorge; Lukas Tamayo Orrego

doi:10.1101/gad.352311.124

CDK4 Loss of Function Mutations Cause Microcephaly and Short Stature

Aitana Verdu Schlie, Maria Izabel Arismendi, Andrea Leitch, Colin Stok, Andrea Castro leal, David A. Parry, Antonio Marcondes Lerário, Margaret Haley, Bruna Lucheze, Paula L Carroll, Kamila Musialik, Julia Auer, Carol-Anne Martin, Lukas Gerasimavicius, Alan J Quigley, Joya Emilie de Menezes Correia-Deur, Joseph A Marsh, Martin A M Reijns, Anne K Lampe, Andrew P Jackson^*Alexander A. L. Jorge^*, Lukas Tamayo Orrego

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Cell number is a major determinant of organism size in mammals. In humans, gene
mutations in cell cycle components result in restricted growth through reduced cell
numbers. Here we identified biallelic mutations in CDK4 as a cause of microcephaly and
short stature. CDK4 encodes a key cell cycle kinase that associates with D-type cyclins during
G1 of the cell cycle to promote S-phase entry and cell proliferation through retinoblastoma
(RB) phosphorylation. CDK4 and CDK6 are believed to be functionally redundant and are
targeted jointly by chemotherapeutic CDK4/6 inhibitors. Using molecular and cell biology
approaches, we show that functional CDK4 protein is not detectable in cells with CDK4
mutations. Cells display impaired RB phosphorylation in G1 leading to G1/S-phase transition
defects and reduced cell proliferation, consistent with complete loss of cellular CDK4
enzymatic activity. Together, these findings demonstrate that CDK4 is itself required for cell
proliferation, human growth and brain size determination during development

Original language	English
Pages (from-to)	634-651
Journal	Genes & Development
Volume	39
Issue number	9-10
Early online date	10 Apr 2025
DOIs	https://doi.org/10.1101/gad.352311.124
Publication status	Published - 2 May 2025

Keywords / Materials (for Non-textual outputs)

Cell Cycle/genetics
Cell Proliferation/genetics
Cyclin-Dependent Kinase 4/genetics
Dwarfism/genetics
Humans
Loss of Function Mutation/genetics
Microcephaly/genetics
Phosphorylation
Retinoblastoma Protein/metabolism

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10.1101/gad.352311.124Licence: Creative Commons: Attribution (CC-BY)

Genes Dev.-2025-Verdu Schlie-634-51Final published version, 3.62 MBLicence: Creative Commons: Attribution (CC-BY)

1 Finished
1 Active

Protein variant interpretation
Marsh, J. (Principal Investigator)
1/04/23 → 31/03/28
Project: Research
MC_UU_00007/5 From Microcephaly to Genome Stability, Inflammation and Growth Regulation
Jackson, A. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

Verdu Schlie, A., Arismendi, M. I., Leitch, A., Stok, C., leal, A. C., Parry, D. A., Lerário, A. M., Haley, M., Lucheze, B., Carroll, P. L., Musialik, K., Auer, J., Martin, C.-A., Gerasimavicius, L., Quigley, A. J., Correia-Deur, J. E. D. M., Marsh, J. A., Reijns, M. A. M., Lampe, A. K., ... Tamayo Orrego, L. (2025). CDK4 Loss of Function Mutations Cause Microcephaly and Short Stature. Genes & Development, 39(9-10), 634-651. https://doi.org/10.1101/gad.352311.124

@article{c7a6b39d885c4b9c9b5aa64dfec860b7,

title = "CDK4 Loss of Function Mutations Cause Microcephaly and Short Stature",

abstract = "Cell number is a major determinant of organism size in mammals. In humans, gene mutations in cell cycle components result in restricted growth through reduced cell numbers. Here we identified biallelic mutations in CDK4 as a cause of microcephaly and short stature. CDK4 encodes a key cell cycle kinase that associates with D-type cyclins during G1 of the cell cycle to promote S-phase entry and cell proliferation through retinoblastoma (RB) phosphorylation. CDK4 and CDK6 are believed to be functionally redundant and are targeted jointly by chemotherapeutic CDK4/6 inhibitors. Using molecular and cell biology approaches, we show that functional CDK4 protein is not detectable in cells with CDK4 mutations. Cells display impaired RB phosphorylation in G1 leading to G1/S-phase transition defects and reduced cell proliferation, consistent with complete loss of cellular CDK4 enzymatic activity. Together, these findings demonstrate that CDK4 is itself required for cell proliferation, human growth and brain size determination during development",

keywords = "Cell Cycle/genetics, Cell Proliferation/genetics, Cyclin-Dependent Kinase 4/genetics, Dwarfism/genetics, Humans, Loss of Function Mutation/genetics, Microcephaly/genetics, Phosphorylation, Retinoblastoma Protein/metabolism",

author = "\{Verdu Schlie\}, Aitana and Arismendi, \{Maria Izabel\} and Andrea Leitch and Colin Stok and leal, \{Andrea Castro\} and Parry, \{David A.\} and Ler{\'a}rio, \{Antonio Marcondes\} and Margaret Haley and Bruna Lucheze and Carroll, \{Paula L\} and Kamila Musialik and Julia Auer and Carol-Anne Martin and Lukas Gerasimavicius and Quigley, \{Alan J\} and Correia-Deur, \{Joya Emilie de Menezes\} and Marsh, \{Joseph A\} and Reijns, \{Martin A M\} and Lampe, \{Anne K\} and Jackson, \{Andrew P\} and Jorge, \{Alexander A. L.\} and \{Tamayo Orrego\}, Lukas",

year = "2025",

month = may,

day = "2",

doi = "10.1101/gad.352311.124",

language = "English",

volume = "39",

pages = "634--651",

journal = "Genes \& Development",

issn = "0890-9369",

publisher = "Cold Spring Harbor Laboratory Press",

number = "9-10",

}

Verdu Schlie, A, Arismendi, MI, Leitch, A, Stok, C, leal, AC, Parry, DA, Lerário, AM, Haley, M, Lucheze, B, Carroll, PL, Musialik, K, Auer, J, Martin, C-A, Gerasimavicius, L, Quigley, AJ, Correia-Deur, JEDM, Marsh, JA , Reijns, MAM, Lampe, AK, Jackson, AP, Jorge, AAL & Tamayo Orrego, L 2025, 'CDK4 Loss of Function Mutations Cause Microcephaly and Short Stature', Genes & Development, vol. 39, no. 9-10, pp. 634-651. https://doi.org/10.1101/gad.352311.124

TY - JOUR

T1 - CDK4 Loss of Function Mutations Cause Microcephaly and Short Stature

AU - Verdu Schlie, Aitana

AU - Arismendi, Maria Izabel

AU - Leitch, Andrea

AU - Stok, Colin

AU - leal, Andrea Castro

AU - Parry, David A.

AU - Lerário, Antonio Marcondes

AU - Haley, Margaret

AU - Lucheze, Bruna

AU - Carroll, Paula L

AU - Musialik, Kamila

AU - Auer, Julia

AU - Martin, Carol-Anne

AU - Gerasimavicius, Lukas

AU - Quigley, Alan J

AU - Correia-Deur, Joya Emilie de Menezes

AU - Marsh, Joseph A

AU - Reijns, Martin A M

AU - Lampe, Anne K

AU - Jackson, Andrew P

AU - Jorge, Alexander A. L.

AU - Tamayo Orrego, Lukas

PY - 2025/5/2

Y1 - 2025/5/2

N2 - Cell number is a major determinant of organism size in mammals. In humans, gene mutations in cell cycle components result in restricted growth through reduced cell numbers. Here we identified biallelic mutations in CDK4 as a cause of microcephaly and short stature. CDK4 encodes a key cell cycle kinase that associates with D-type cyclins during G1 of the cell cycle to promote S-phase entry and cell proliferation through retinoblastoma (RB) phosphorylation. CDK4 and CDK6 are believed to be functionally redundant and are targeted jointly by chemotherapeutic CDK4/6 inhibitors. Using molecular and cell biology approaches, we show that functional CDK4 protein is not detectable in cells with CDK4 mutations. Cells display impaired RB phosphorylation in G1 leading to G1/S-phase transition defects and reduced cell proliferation, consistent with complete loss of cellular CDK4 enzymatic activity. Together, these findings demonstrate that CDK4 is itself required for cell proliferation, human growth and brain size determination during development

AB - Cell number is a major determinant of organism size in mammals. In humans, gene mutations in cell cycle components result in restricted growth through reduced cell numbers. Here we identified biallelic mutations in CDK4 as a cause of microcephaly and short stature. CDK4 encodes a key cell cycle kinase that associates with D-type cyclins during G1 of the cell cycle to promote S-phase entry and cell proliferation through retinoblastoma (RB) phosphorylation. CDK4 and CDK6 are believed to be functionally redundant and are targeted jointly by chemotherapeutic CDK4/6 inhibitors. Using molecular and cell biology approaches, we show that functional CDK4 protein is not detectable in cells with CDK4 mutations. Cells display impaired RB phosphorylation in G1 leading to G1/S-phase transition defects and reduced cell proliferation, consistent with complete loss of cellular CDK4 enzymatic activity. Together, these findings demonstrate that CDK4 is itself required for cell proliferation, human growth and brain size determination during development

KW - Cell Cycle/genetics

KW - Cell Proliferation/genetics

KW - Cyclin-Dependent Kinase 4/genetics

KW - Dwarfism/genetics

KW - Humans

KW - Loss of Function Mutation/genetics

KW - Microcephaly/genetics

KW - Phosphorylation

KW - Retinoblastoma Protein/metabolism

U2 - 10.1101/gad.352311.124

DO - 10.1101/gad.352311.124

M3 - Article

C2 - 40210435

SN - 0890-9369

VL - 39

SP - 634

EP - 651

JO - Genes & Development

JF - Genes & Development

IS - 9-10

ER -

CDK4 Loss of Function Mutations Cause Microcephaly and Short Stature

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

Protein variant interpretation

MC_UU_00007/5 From Microcephaly to Genome Stability, Inflammation and Growth Regulation

Cite this