Insertion of 16 amino acids in the BAR domain of the oligophrenin 1 protein causes mental retardation and cerebellar hypoplasia in an Italian family

Filomena Pirozzi, Francesca Romana Di Raimo, Ginevra Zanni, Enrico Bertini, Pierre Billuart, Tommaso Tartaglione, Elisabetta Tabolacci, Andrea Brancaccio, Giovanni Neri, Pietro Chiurazzi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

We observed a three-generation family with two maternal cousins and an uncle affected by mental retardation (MR) with cerebellar hypoplasia. X-linked inheritance and the presence of cerebellar malformation suggested a mutation in the OPHN1 gene. In fact, mutational screening revealed a 2-bp deletion that abolishes a donor splicing site, resulting in the inclusion of the initial 48 nucleotides of intron 7 in the mRNA. This mutation determines the production of a mutant oligophrenin 1 protein with 16 extra amino acids inserted in-frame in the N-terminal BAR (Bin1/amphiphysin/Rvs167) domain. This is the first case of a mutation in OPHN1 that does not result in the production of a truncated protein or in its complete loss. OPHN1 (ARHGAP41) encodes a GTPase-activating (GAP) protein belonging to the GRAF subfamily characterized by an N-terminal BAR domain, followed by a pleckstrin-homology (PH) domain and the GAP domain. GRAF proteins play a role in endocytosis and are supposed to dimerize via their BAR domain, that induces membrane curvature. The extra 16 amino acids cause the insertion of 4.4 turns in the third alpha-helix of the BAR domain and apparently impair the protein function. In fact, the clinical phenotype of these patients is identical to that of patients with loss-of-function mutations.

Original languageEnglish
JournalHuman Mutation
Volume32
Issue number11
DOIs
Publication statusPublished - Nov 2011

Fingerprint

Intellectual Disability
GTPase-Activating Proteins
Amino Acids
Mutation
Proteins
X-Linked Genes
Endocytosis
Introns
Nucleotides
Mothers
Tissue Donors
Phenotype
Messenger RNA
Membranes
amphiphysin
Cerebellar Hypoplasia
Genes

Keywords

  • BAR domain
  • Cerebellar hypoplasia
  • OPHN1 gene
  • Subcortical atrophy
  • X-linked mental retardation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Insertion of 16 amino acids in the BAR domain of the oligophrenin 1 protein causes mental retardation and cerebellar hypoplasia in an Italian family. / Pirozzi, Filomena; Di Raimo, Francesca Romana; Zanni, Ginevra; Bertini, Enrico; Billuart, Pierre; Tartaglione, Tommaso; Tabolacci, Elisabetta; Brancaccio, Andrea; Neri, Giovanni; Chiurazzi, Pietro.

In: Human Mutation, Vol. 32, No. 11, 11.2011.

Research output: Contribution to journalArticle

Pirozzi, Filomena ; Di Raimo, Francesca Romana ; Zanni, Ginevra ; Bertini, Enrico ; Billuart, Pierre ; Tartaglione, Tommaso ; Tabolacci, Elisabetta ; Brancaccio, Andrea ; Neri, Giovanni ; Chiurazzi, Pietro. / Insertion of 16 amino acids in the BAR domain of the oligophrenin 1 protein causes mental retardation and cerebellar hypoplasia in an Italian family. In: Human Mutation. 2011 ; Vol. 32, No. 11.
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