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Intellectual disability

Gene: MPP5

Amber List (moderate evidence)

MPP5 (membrane palmitoylated protein 5)
EnsemblGeneIds (GRCh38): ENSG00000072415
EnsemblGeneIds (GRCh37): ENSG00000072415
OMIM: 606958, Gene2Phenotype
MPP5 is in 2 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: New gene added by Konstantinos Varvagiannis. ased on the evidence provided in PMID:33073849, this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag) - 3 unrelated individuals with de novo variants in the MPP5 gene associated with ID/GDD, language delay/regression and behavioural changes. Supportive animal model.
Created: 20 Nov 2020, 2:24 p.m. | Last Modified: 20 Nov 2020, 2:24 p.m.
Panel Version: 3.562

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Sterling et al (2020 - PMID: 33073849) provide information on the phenotype of 3 individuals with de novo MPP5 variants.

Common features included global developmental delay, intellectual disability (3/3 - severe in 2/3), speech delay/regression (the latter in at least 2) and behavioral abnormalities. Variable other features were reported, among others microcephaly (1/3), abnormal vision (1/3 : CVI, retinal dystrophy, nystagmus), brain MRI abnormalities (2/3), late-onset seizures (1/3). These subjects displayed variable and non-specific dysmorphic features.

All were investigated by exome sequencing (previous tests not mentioned).

One subject was found to harbor a de novo mosaic (5/25 reads) stopgain variant, further confirmed by Sanger sequencing [NM_022474.4:c.1555C>T - p.(Arg519Ter). The specific variant is reported once in gnomAD (1/251338). Two de novo missense variants were identified in the remaining individuals [c.1289A>G - p.Glu430Gly / c.974A>C - p.His325Pro).

All variants had in silico predictions in favor of a deleterious effect (CADD score >24).

The authors comment that MPP5 encodes an apical complex protein with asymmetric localization to the apical side of polarized cells. It is expressed in brain, peripheral nervous system and other tissues. MPP5 is a member of the membrane-associated guanylate kinase family of proteins (MAGUK, p55 subfamily), determining cell polarity at tight junctions.

Previous animal models suggest that complete Mpp5(Pals1) KO in mice leads to near absence of cerebral cortical neurons. Htz KO mice display reduction in size of cerebral cortex and hippocampus. The gene is expressed in proliferating cell populations of cerebellum and important for establishment cerebellar architecture. Conditional KO of Mpp5(Pals1) in retinal progenitor cells mimics the retinal pathology observed in LCA. [Several refs. provided]

The authors studied a heterozygous CNS-specific Mpp5 KO mouse model. These mice presented microcephaly, decreased cerebellar volume and cortical thickness, decreased ependymal cells and Mpp5 at the apical surface of cortical vertrical zone. The proportion of cortical cells undergoing apoptotic cell death was increased. Mice displayed behavioral abnormalities (hyperactivity) and visual deficits, with ERG traces further suggesting retinal blindness.

Overall the mouse model was thought to recapitulate the behavioral abnormalities observed in affected subjects as well as individual rare features such as microcephaly and abnormal vision.

Haploinsufficiency (rather than a dominant negative effect) is favored as the underlying disease mechanism. This is also in line with a dose dependent effect observed in mice.
Sources: Literature
Created: 1 Nov 2020, 7:45 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Delayed speech and language development
  • Developmental regression
  • Behavioral abnormality
Tags
for-review
OMIM
606958
Clinvar variants
Variants in MPP5
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

20 Nov 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: mpp5 has been classified as Amber List (Moderate Evidence).

20 Nov 2020, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: MPP5.

1 Nov 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: MPP5 was added gene: MPP5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: MPP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MPP5 were set to 33073849 Phenotypes for gene: MPP5 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Developmental regression; Behavioral abnormality Penetrance for gene: MPP5 were set to unknown Review for gene: MPP5 was set to GREEN