Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy

Abstract

Heterozygous in-frame mutations (p.E2207del and p.R2308_M2309dup) in the a-II subunit of spectrin (SPTAN1) were recently identified in two patients with intellectual disability (ID), infantile spasms (IS), hypomyelination, and brain atrophy. These mutations affected the C-terminal domain of the protein, which contains the nucleation site of the a/b spectrin heterodimer. By screening SPTAN1 in 95 patients with idiopathic ID, we found a de novo in-frame mutation (p.Q2202del) in the same C-terminal domain in a patient with mild generalized epilepsy and pontocerebellar atrophy, but without IS, hypomyelination, or other brain structural defects, allowing us to define the core phenotype associated with these C-terminal SPTAN1 mutations. We also found a de novo missense variant (p.R566P) of unclear clinical significance in a patient with non-syndromic ID. These two mutations induced different patterns of aggregation between spectrin subunits in transfected neuronal cell lines, providing a paradigm for the classification of candidate variants. European Journal of Human Genetics (2012) 20, 796-800; doi:10.1038/ejhg.2011.271; published online 18 January 2012 Keywords: intellectual disability; epilepsy; SPTAN1; pontocerebellar atrophy INTRODUCTIONThe targeting and maintenance of groups of proteins at specific membrane domains of neurons, such as the synapse and the axon, are critical for the brain function and development. Not surprisingly, mutations in proteins that participate in the assembling of these domains, such as the spectrins, have been shown to cause neurological disorders. Spectrins consist of a-and b-subunits that form antiparallel heterodimers, which are assembled to form heterotetramers in a headto-head configuration. 1,2 Heterozygous mutations in the b-III subunit (SPTBN2) were shown to cause spinocerebellar ataxia type-5. 3 Recently, de novo in-frame mutations in the a-II spectrin subunit (SPTAN1) were identified in patients with severe intellectual disability (ID), infantile spasms (IS) with hypsarrhythmia, hypomyelination, and atrophy of various regions of the brain, including the cerebellum and brainstem. 4 These mutations are located in a C-terminal domain that includes the nucleation site involved in a/b spectrin heterodimer formation. 5 Biochemical studies indicated that these mutations destabilized this interaction, leading to aggregation of a-II(mut)/b-II and a-II(mut)/b-III spectrin heterodimers in mouse cortical neurons and in lymphoblastoid cells from the patients. 4 Recent studies suggest that de novo point mutations in the germ line, which in humans are estimated to occur at a rate of B1.1Â10 À8 per base, may explain a large fraction of ID cases. [6][7][8] In the course of a project aimed to identify such mutations in candidate synaptic genes,

SPTAN1 encephalopathy: distinct phenotypes and genotypes

“…Furthermore, in primary neuronal cultures, the p.Q2202 del mutation showed a similar aggregation profile, but in a lower proportion of cells. 23 These expression data suggest that the degree of aggregation involving α-II/β-II and α-II/β-III spectrin heterodimers could correlate with the severity of clinical symptoms. It is also notable that two patients (subjects 2 and 4) with a duplication mutation in the last spectrin repeat passed away early in childhood.…”

“…A total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified to date. Interestingly, Hamdan et al 23 also reported a de novo p.R566P mutation in a patient with mild nonsyndromic ID without epilepsy. The pathological significance of this missense mutation is unclear because the patient's sister, who has similar clinical features, does not carry the SPTAN1 mutation.…”

“…Only atrophy of brainstem and cerebellum are observed in subject 7. 23 Images of i and j are adapted from ref. 23.…”

“…Whole-exome sequencing (WES) unexpectedly revealed a SPTAN1 mutation in subject 5, in whom a SPTAN1 mutation was never suspected. In addition to West syndrome, Hamdan et al 23 identified an in-frame de novo SPTAN1 mutation (c.6605_6607 del; p.Q2202 del) within the continuous helix region between the last two spectrin repeats in a patient with generalized epilepsy, intellectual disability (ID) and pontocerebellar atrophy. A total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified to date.…”

“…The pathological significance of this missense mutation is unclear because the patient's sister, who has similar clinical features, does not carry the SPTAN1 mutation. 23 Therefore, in this review, we are focusing on patients with in-frame SPTAN1 mutations, who showed epileptic encephalopathy or epilepsy.…”