Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul;59(7):662-668.
doi: 10.1136/jmedgenet-2021-107843. Epub 2021 Jun 18.

Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive

Guido Vogt  1 , Sarah Verheyen  2 , Sarina Schwartzmann  1 , Nadja Ehmke  1 , Cornelia Potratz  3 , Anette Schwerin-Nagel  4 , Barbara Plecko  4 , Manuel Holtgrewe  5 , Dominik Seelow  1   6 , Jasmin Blatterer  2 , Michael R Speicher  2 , Uwe Kornak  1   7 , Denise Horn  1 , Stefan Mundlos  1   8 , Björn Fischer-Zirnsak  1   8 , Felix Boschann  9
Affiliations

Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive

Guido Vogt et al. J Med Genet. 2022 Jul.

Abstract

Background: Genes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM).

Methods: Exome sequencing was performed in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants.

Results: We detected homozygous truncating variants in ATP9A. While the variant in family A is predicted to result in an early premature termination codon, the variant in family B affects a canonical splice site. Both variants lead to a substantial reduction of ATP9A mRNA expression. It has been shown previously that ATP9A localises to early and recycling endosomes, whereas its depletion leads to altered gene expression of components from this compartment. Consistent with previous findings, we also observed overexpression of ARPC3 and SNX3, genes strongly interacting with ATP9A.

Conclusion: In aggregate, our findings show that pathogenic variants in ATP9A cause a novel autosomal recessive neurodevelopmental disorder with POM. While the physiological function of endogenous ATP9A is still largely elusive, our results underline a crucial role of this gene in endosomal transport in brain tissue.

Keywords: DNA; RNA; and neonatal diseases and abnormalities; congenital; genetics; hereditary; medical; sequence analysis.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
(A) Clinical appearance of the three affected individuals. A-II-1: at the age of 12 years, our proband showed microcephaly, esotropia, a smooth philtrum and a thin upper lip vermilion. A-II-2: his brother, aged 4 years, with smooth philtrum and thin lips. B-II-1: at the age of 10 years, the individual from family B displayed microcephaly, a thin upper lip and a smooth philtrum. (B) Integrative Genomics Viewer screenshot of exome sequencing showing the variants in ATP9A (NM_006045.3): homozygous nonsense variant c.868C>T, p.(Arg290*) in individual A-II-1 and homozygous intronic variant c.642+1G>A in individual B-II-1. Pedigree showing the segregation of the variants within the two families.
Figure 2
Figure 2
(A) Direct sequencing of cDNA of individual B-II-1 confirmed that the splice variant results in skipping of exon 7 (r.547_642del). This deletion is predicted to result in a frameshift and premature stop of translation p.(Ser184Profs*16). (B) Quantitative PCR revealed strongly reduced ATP9A mRNA expression in skin fibroblasts of the affected individuals A-II-1 and B-II-1 compared with controls C1, C2 and C3. ***P<0.0005 (quantified by Student’s t-test). (C) Protein domains of ATP9A (O75110) and schematic representation of the synthesised truncated protein in case of nonsense-mediated mRNA decay escape.
Figure 3
Figure 3
(A) qPCR detected overexpression of ARPC3 [HGNC:706; NM_001278556] in patient-derived fibroblasts compared with controls. (B) Upregulation of SNX3 mRNA expression levels [HGNC:11174; NM_003795] in patients fibroblast compared with controls. *P<0.05, *P<0.005, ***P<0.0005 (quantified by Student’s t-test).
See this image and copyright information in PMC

References

    1. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil 2011;32:419–36. 10.1016/j.ridd.2010.12.018 - DOI - PubMed
    1. Vissers LELM, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet 2016;17:9–18. 10.1038/nrg3999 - DOI - PubMed
    1. Liu P, Meng L, Normand EA, Xia F, Song X, Ghazi A, Rosenfeld J, Magoulas PL, Braxton A, Ward P, Dai H, Yuan B, Bi W, Xiao R, Wang X, Chiang T, Vetrini F, He W, Cheng H, Dong J, Gijavanekar C, Benke PJ, Bernstein JA, Eble T, Eroglu Y, Erwin D, Escobar L, Gibson JB, Gripp K, Kleppe S, Koenig MK, Lewis AM, Natowicz M, Mancias P, Minor L, Scaglia F, Schaaf CP, Streff H, Vernon H, Uhles CL, Zackai EH, Wu N, Sutton VR, Beaudet AL, Muzny D, Gibbs RA, Posey JE, Lalani S, Shaw C, Eng CM, Lupski JR, Yang Y. Reanalysis of clinical exome sequencing data. N Engl J Med 2019;380:2478–80. 10.1056/NEJMc1812033 - DOI - PMC - PubMed
    1. Kochinke K, Zweier C, Nijhof B, Fenckova M, Cizek P, Honti F, Keerthikumar S, Oortveld MAW, Kleefstra T, Kramer JM, Webber C, Huynen MA, Schenck A. Systematic phenomics analysis Deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am J Hum Genet 2016;98:149–64. 10.1016/j.ajhg.2015.11.024 - DOI - PMC - PubMed
    1. Boonsawat P, Joset P, Steindl K, Oneda B, Gogoll L, Azzarello-Burri S, Sheth F, Datar C, Verma IC, Puri RD, Zollino M, Bachmann-Gagescu R, Niedrist D, Papik M, Figueiro-Silva J, Masood R, Zweier M, Kraemer D, Lincoln S, Rodan L, Passemard S, Drunat S, Verloes A, Horn AHC, Sticht H, Steinfeld R, Plecko B, Latal B, Jenni O, Asadollahi R, Rauch A, Undiagnosed Diseases Network (UDN) . Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Genet Med 2019;21:2043–58. 10.1038/s41436-019-0464-7 - DOI - PMC - PubMed

Publication types

Substances

LinkOut - more resources