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. 2016 Sep 29;11(1):130.
doi: 10.1186/s13023-016-0509-9.

SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss

Rebecca Buchert  1   2 , Addie I Nesbitt  3 , Hasan Tawamie  1 , Ian D Krantz  4 , Livija Medne  5 , Ingo Helbig  6   7 , Dena R Matalon  4 , André Reis  1 , Avni Santani  3   8 , Heinrich Sticht  9 , Rami Abou Jamra  10   11
Affiliations

SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss

Rebecca Buchert et al. Orphanet J Rare Dis. .

Abstract

We examined an extended, consanguineous family with seven individuals with severe intellectual disability and microcephaly. Further symptoms were hearing loss, vision impairment, gastrointestinal disturbances, and slow and asymmetric waves in the EEG. Linkage analysis followed by exome sequencing revealed a homozygous variant in SPATA5 (c.1822_1824del; p.Asp608del), which segregates with the phenotype in the family. Molecular modelling suggested a deleterious effect of the identified alterations on the protein function. In an unrelated family, we identified compound heterozygous variants in SPATA5 (c.[2081G > A];[989_991delCAA]; p.[Gly694Glu];[.Thr330del]) in a further individual with global developmental delay, infantile spasms, profound dystonia, and sensorineural hearing loss. Molecular modelling suggested an impairment of protein function in the presence of both variants.SPATA5 is a member of the ATPase associated with diverse activities (AAA) protein family and was very recently reported in one publication to be mutated in individuals with intellectual disability, epilepsy and hearing loss. Our results describe new, probably pathogenic variants in SPATA5 that were identified in individuals with a comparable phenotype. We thus independently confirm that bi-allelic pathogenic variants in SPATA5 cause a syndromic form of intellectual disability, and we delineate its clinical presentation.

Keywords: ARID; Hearing loss; Hypotonia; Microcephaly; NGS.

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Figures

Fig. 1
Fig. 1
Pedigree and pictures of family MR003
Fig. 2
Fig. 2
a Pedigree and picture of family B. b Schematic structure of SPATA5 and identified alterations. Previously reported variants are indicated in black, the variants identified in this study c.1822_1824del; p.Asp608del, c.2081G > A; p.Gly694Glu and c.989_991delCAA; p.Thr330del are indicated in red
Fig. 3
Fig. 3
Structure of the AAA ATPase domains of SPATA5. a Model of the hexameric quaternary structure of SPATA5 showing the individual subunits in different colours. ADP-molecules bound to the ATPase domains are shown in stick presentation and coloured according to their atom type. p.Asp608 and p.Gly608Glu are located at the subunit interface and are depicted as black and magenta balls, respectively. pThr330 is located N-terminally adjacent to the globular domain and is shown as brown ball. b Enlargement showing the stabilizing interactions of p.Asp608 (D608) with p.Lys517 (K517) of the adjacent subunit (both residues are shown in stick presentation). The salt-bridge between both residues is shown in green and the subunits are coloured in red and blue respectively. c Deletion of p.Asp608 (D608) results in a loss of the helical secondary structure (pink arrow) and of the intersubunit salt-bridge. d Enlargement showing the location of pGly694 (G694) at the subunit interface. e Replacement of p.Gly544 by glutamate (E694) results in electrostatic repulsion (black arrow) with p.Asp630 (D630) of the adjacent subunit
See this image and copyright information in PMC

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