Evaluating the Role of MAST1 as an Intellectual Disability Disease Gene: Identification of a Novel De Novo Variant in a Patient with Developmental Disabilities

  • Afif Ben-Mahmoud
  • Aisha M. Al-Shamsi
  • Bassam R. Ali
  • Lihadh Al-GazaliEmail author


Intellectual disability (ID) is one of the most common developmental disorders characterized by a congenital limitation in intellectual functioning and adaptive behavior. More than 800 genes have been implicated so far in the pathogenesis of syndromic and non-syndromic ID conditions with the actual number is expected to be over two thousand. The advent of next-generation sequencing resulted in the identification of many novel ID genes with new genes are being reported on weekly basis. The level of evidence on ID genes varies with some of them being preliminary. MAST1 have been hinted at as being causative of ID but the evidence has been very sketchy. Extensive search of the literature identified three heterozygous de novo missense variants in MAST1 as possible causes of syndromic ID in three individuals where intellectual disability has been a major feature. Using exome sequencing, we identified a novel missense variant c.3539T>G, p.(Leu1180Arg) in MAST1 in an Emirati patient with intellectual disability, microcephaly, and dysmorphic features. In silico pathogenicity prediction analyses predict that all the four missense variants reported in this study are likely to be damaging. Immunostaining of cells expressing human MAST1 showed that majority large proportion of the expressed protein is colocalized the microtubule filaments in the cytoplasm. However, the identified variant c.3539T>G, p.(Leu1180Arg) as well as the other three variants seem to localize in a similar pattern to wild-type indicating a disease mechanism not involving mis-targeting. We, therefore, suggest that mutations in MAST1 should be considered as strong candidates for intellectual disability in humans.


MAST1 Whole-exome sequencing Intellectual disability Novel candidate gene Subcellular localization 



intellectual disability


microtubule associated serine/threonine kinase type 1


developmental delay/intellectual disability


developmental delay/mental retardation


syntrophin-associated serine/threonine kinase


copy number variants


autism spectrum disorders


single-nucleotide variant


Al-Ain Medical Human Research Ethics Committee


comparative genomic hybridization

low IQ

low intelligence quotient


phosphatase and tensin homolog


dystrophin- and utrophin-associated protein complexes.



Special thanks to the family described in this report for their willingness to participate in this study. We are also indebted to the Genotyping and Sequencing core Facilities for their technical help. We are grateful to Mr. Saeed Tariq, from the confocal facility core at the College of Medicine and Health Sciences for his help with confocal microscopy imaging. We would also like to thank United Arab Emirates University for funding this work (grant numbers 31R184 and 31R126).

Compliance with Ethical Standards

The study was approved by Al-Ain Medical Human Research Ethics Committee (AMHREC) according to the national regulations (approval code ERH-2015-3241 15-115).

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

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Figure S1

Genomic structure of MAST1 and multiple protein sequence alignments. (a) MAST1 is composed of 26 coding exons. Location of the missense variants analyzed in this study is indicated by asterisks. c.278C > T, p.(Ser93Leu) in exon 4, c.1499C > T, p.(Pro500Leu) in exon 13 and the two close missense variants c.3530C > G, p.(Pro1177Arg) and c.3539 T > G, p.(Leu1180Arg) in the last exon of MAST1. (Lower diagram) Schematic representation of the entire amino acid sequence of the PDZ domain followed by the downstream amino acid sequence of MAST1 protein showing the position of the two close missense variants Pro1177Arg and Leu1180Arg (marked in red). Multiple protein sequence alignments of MAST1 from different species revealed that residues Ser93 (b) and Pro500 (c) (boxed in red), were located within a highly conserved region. (PNG 196 kb)

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High Resolution Image (TIF 606 kb)
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Figure S2

MAST1 missense variants exhibit similar subcellular localization as the wild-type protein. Subcellular localization was examined by immunofluorescence analysis under confocal laser scanning microscopy. Cells were cultured in chamber slides, fixed with methanol, transfected with plasmids encoding myc-tagged MAST1 (either wild-type or the indicated mutant variants) and processed for immunocytochemistry as described in ‘Subject and Methods’. Cells were stained with antibodies against myc-tag (red) and α Tubulin (B-7) (green). The majority significant proportion of the expressed protein is colocalized the microtubule filaments in the cytoplasm (panel a). Merged fluorescence shows that the four missense variants do not strongly differs from that of the MAST1-WT. We conclude that no major alterations in intracellular trafficking of MAST1 protein were caused by the four missense variants (Panels b, c, d and e). The scale bar represents 25 μm and applies to all the panels. The data for the HEK293 cell lines are not shown but were always consistent with the HeLa cell line results. (PNG 1077 kb)

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High Resolution Image (TIF 2640 kb)
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ESM 1 (DOCX 16 kb)
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Table S1

Primers sequence used for site-directed mutagenesis (PNG 96 kb)

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High Resolution Image (TIF 284 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Genetics and Genomics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
  2. 2.Zayed Center for Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
  3. 3.Department of Pediatrics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates

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