Alternative titles; symbols
HGNC Approved Gene Symbol: SPTAN1
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:128,552,587-128,633,662 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Developmental and epileptic encephalopathy 5 | 613477 | Autosomal dominant | 3 |
| Developmental delay with or without epilepsy | 620540 | Autosomal dominant | 3 | |
| Neuronopathy, distal hereditary motor, autosomal dominant 11 | 620528 | Autosomal dominant | 3 | |
| Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia | 620538 | Autosomal dominant | 3 |
The spectrins, including nonerythrocytic alpha-spectrin-1 (SPTAN1), are a family of widely-distributed filamentous cytoskeletal proteins which have a highly conserved 106-amino acid repeat structure. Spectrins are heterodimers of a constant alpha-chain and variable tissue-specific beta-chains. Functions of these proteins include regulation of receptor binding and actin crosslinking (Leto et al., 1988).
McMahon et al. (1987) cloned SPTAN1, which they termed alpha-fodrin, from a human lung fibroblast cDNA library. From this, they compared the structure of alpha-spectrin (SPTA1; 182860) and alpha-fodrin with deductions as to their evolution. The alpha-fodrin protein contains a 106-residue repeating structure, which is homologous with alpha-spectrin repeats 7 to 15. A 9-kb transcript was identified. A comparison of nucleic acid and amino acid homologies between alpha-spectrin and alpha-fodrin of several vertebrate species indicated that human nonerythroid alpha-fodrin and the common alpha-subunit of erythroid and nonerythroid cells of nonmammalian vertebrates are closely related (90-96% amino acid homology), whereas alpha-fodrin is only distantly related to the erythroid-specific alpha-spectrin subunit of mammals (55-59% amino acid homology). These data suggested that mammalian erythroid alpha-spectrin evolved by duplication and rapid divergence from an ancestral alpha-fodrin-like gene.
Leto et al. (1988) used a probe for nonerythroid alpha-spectrin derived from a rat brain cDNA library to isolate the corresponding gene in man. They found close similarity of nonerythroid alpha-spectrin sequences in diverse species.
Cianci et al. (1999) cloned a full-length SPTAN1 cDNA from a human fetal brain library. The deduced 2,477-residue protein has a predicted molecular mass of 285 kD. The protein contains 21 spectrin repeat units, a central SH3 domain, and a C-terminal EF-hand domain. They noted that the fundamental structural feature of the conserved spectrin repeat unit is a triple alpha-helical motif. In addition to 11 amino acid substitutions that differed from the transcript in human lung fibroblasts and likely represent polymorphisms, the human fetal brain SPTAN1 also had a 5-residue (15-bp) insertion in repeat unit 15 that arose from alternative splicing. Examination of several different mouse tissues demonstrated that the 5-residue insertion was found only in brain, heart, skeletal muscle, and embryonic tissues, while other isoforms were more widely distributed. Combined with other insertions, Cianci et al. (1999) predicted that at least 4, and as many as 8, different splice forms of the mature protein may be generated.
Zhang et al. (2010) identified 2 novel alternatively spliced Sptan1 transcripts expressed only in the developing rat heart muscle. The transcripts contained a 21-residue insert in repeat 21 near the C terminus that was designated alpha-II-cardi+. The unique sequence occurs within the high affinity nucleation site for binding of alpha-II-spectrin to beta-spectrin, causing decreased binding, as shown by functional expression studies. Zhang et al. (2010) noted that 10 Sptan1 transcripts have now been identified in rat heart tissue.
Saitsu et al. (2010) stated that the SPTAN1 gene contains 57 exons.
By somatic cell hybrid studies and in situ hybridization, Barton et al. (1987) and Leto et al. (1988) mapped the SPTAN1 gene to chromosome 9q33-q34.
Birkenmeier et al. (1988) showed that the brain alpha-spectrin gene is located on the centromeric end of mouse chromosome 2 and is not closely linked to any known erythroid or neurologic mutation. They symbolized this gene in the mouse as Spna-2.
Metral et al. (2009) found that downregulation of SPTAN1 using small interfering RNA in cultured human melanoma cells resulted in alterations of the cell shape, with spectrin-depleted cells being much smaller, rounded, and less spread out. These changes were associated with disorganization of the actin cytoskeleton and reduction of the basal stress fibers network. There was also a progressive decrease in cell adhesion. Spectrin loss inhibited cell proliferation via arrest at cell cycle phase G1, which was associated with upregulation of the cyclin-dependent kinase inhibitor p21 (CDKN1A; 116899).
Developmental and Epileptic Encephalopathy 5
In 2 unrelated Japanese patients with developmental and epileptic encephalopathy-5 (DEE5; 613477), previously reported by Tohyama et al. (2008), Saitsu et al. (2010) identified 2 different de novo heterozygous mutations in the SPTAN1 gene (182810.0001 and 182810.0002). One mutation was an in-frame deletion and the other was an in-frame duplication. Both occurred in the last 2 spectrin repeats at the C terminus. In vitro functional expression studies suggested a dominant-negative effect of the mutations on spectrin heterodimer stability, as well as perturbation of the axon initial segment.
In an 11-year-old French Canadian boy with DEE5, Hamdan et al. (2012) identified a de novo heterozygous mutation in the SPTAN1 gene (182810.0003). The mutation resulted in an in-frame deletion at the C terminus required for alpha/beta spectrin subunit heterodimer formation. In vitro expression of the mutation in primary mouse cortical neurons caused formation of spectrin aggregates in about 20% of cells.
In a 12-month-old Japanese boy with DEE5, who had a clinical diagnosis of West syndrome, Nonoda et al. (2013) identified a de novo heterozygous in-frame duplication in the last spectrin repeat of the SPTAN1 gene (182810.0005).
In a 3-year-old girl (P9) with DEE5, Syrbe et al. (2017) identified a de novo heterozygous missense mutation in the SPTAN1 gene (E2271K; 182810.0015). The mutation occurred in the last spectrin repeat domain (20) in the alpha/beta heterodimerization domain at the C terminus, likely disrupting this interaction. Morsy et al. (2023) also identified a de novo heterozygous E2271K mutation in the SPTAN1 gene in a 12-year-old boy (P28) with DEE5. Functional studies of the variant and studies of patient cells were not performed. This mutation is a rare missense mutation in the C terminus of the gene associated with DEE5. Most DEE5-related mutations occur at the C terminus, but cause in-frame duplications or deletions.
In 14 unrelated patients with DEE5, Syrbe et al. (2017) identified heterozygous, mostly de novo, mutations in the SPTAN1 gene (see, e.g., 182810.0001; 182810.0002; 182810.0005; and 182810.0015). Most mutations occurred in spectrin repeats 19 and 20 at the C terminus. However, 2 patients had missense mutations (R1776W and R2062W) that occurred in spectrin repeats 14 and 16. R2062W is absent from gnomAD, but R1776W occurred once in gnomAD. The patient (P19) with the R1776W mutation had a mild form of the disorder.
Morsy et al. (2023) reported 5 unrelated patients with DEE5 (P27-P31) associated with heterozygous, mostly de novo, mutations in the SPTAN1 gene (see, e.g., 182810.0001; 182810.0005; 182810.0014; 182810.0015). Four of the mutations occurred in the C-terminal alpha/beta dimerization domain. One mutation (c.4344G-A), resulted in a splice site mutation in spectrin repeat 13.
Distal Hereditary Motor Neuronopathy, Autosomal Dominant 11
In 12 affected individuals from 3 unrelated families with autosomal dominant distal hereditary motor neuronopathy-11 (HMND11; 620528), Beijer et al. (2019) identified heterozygous nonsense mutations in the SPTAN1 gene (see, e.g., 182810.0006 and 182810.0007). The mutations, which were found by whole-genome or whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and were not present in the ExAC or gnomAD databases. Western blot analysis of patient lymphoblasts showed decreased SPTAN1 protein levels at about 60 to 80% compared to noncarriers due to nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency. Both patient cells and control cells showed mostly soluble SPTAN1, although there was a clear insoluble fraction in both cell lines. Patient fibroblasts showed normal localization of SPTAN1 in small puncta throughout the cytoplasm with no aggregates, similar to controls. Beijer et al. (2019) noted that although there are a number of heterozygous predicted loss-of-function (LOF) SPTAN1 variants in the gnomAD database, there is still very high intolerance for LOF in this gene. It is possible that individuals with these variants in gnomAD may be only mildly affected or asymptomatic due to incomplete penetrance.
In a 20-year-old man with HMND11, Ylikallio et al. (2020) identified a de novo heterozygous frameshift mutation in the SPTAN1 gene (182810.0008). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD, Exome Sequencing Project, or 1000 Genomes Project databases. Patient cells were not available for study, but the mutation was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.
In a 21-year-old Han Chinese woman with HMND11, Dong et al. (2021) identified a de novo heterozygous nonsense mutation in the SPTAN1 gene (R2261X; 182810.0009). The mutation, which was found by whole-exome sequencing, was not present in the ExAC, dbSNP, 1000 Genomes Project, or gnomAD databases. Studies of HEK293 cells transfected with the mutation showed that it triggered nonsense-mediated mRNA decay, consistent with haploinsufficiency.
Spastic Paraplegia 91 with or without Cerebellar Ataxia, Autosomal Dominant
In affected members of 7 unrelated families (families E-K) with autosomal dominant spastic paraplegia-91 with or without cerebellar ataxia (SPG91; 620538), Van de Vondel et al. (2022) identified a heterozygous missense mutation in the SPTAN1 gene (R19W; 182810.0013) in the N-terminal domain. The mutation, which was found by whole-exome or whole-genome sequencing, segregated with the disorder in the families from whom parental DNA was available. The mutation in at least 1 case (family F) was demonstrated to have occurred de novo. One large family (family K) contained 10 affected individuals spanning 3 generations who were found to carry the mutation. Van de Vondel et al. (2022) also identified a recurrent heterozygous 3-bp in-frame deletion (K2083del; 182810.0014) in the SPTAN1 gene in 4 unrelated patients (families A-D) with SPG91 and more predominant cerebellar ataxia and intellectual disability (in 3). This mutation affected the seventeenth spectrin domain. None of the patients had a family history of the disorder, and the mutations were demonstrated to have occurred de novo in 2 patients. Three additional patients (families L, M, and N) carried de novo heterozygous missense SPTAN1 mutations (R1098C, R1624C, and Q2205P). These patients had congenital symptom onset and primarily cerebellar ataxia; 2 had impaired intellectual development and epilepsy. None of the mutations were present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling suggested that the mutations would result in destabilization of spectrin repeats by interfering with interhelical electrostatic interactions.
Morsy et al. (2023) reported 6 patients from 4 unrelated families (families 1-4) with SPG91 associated with a heterozygous R19W mutation. The mutation in family 2 (3 affected individuals) showed autosomal dominant transmission. The mutation in the patient from family 4 occurred de novo; the single patients in families 1 and 3 had sporadic disease, but the unaffected parents were not sequenced. Fibroblasts derived from 1 patient showed normal protein levels. Immunofluorescent studies showed intense irregular expression and aggregation of SPTAN1 throughout the patient cells that was not observed in control cells. Four additional unrelated individuals with SPG and/or cerebellar ataxia (families 5-8) were also found to carry heterozygous variants in the SPTAN1 gene (2 missense variants, 1 in-frame deletion, and 1 splice site variant), but familial segregation studies and functional studies of the variants were not performed.
Developmental Delay with or without Epilepsy
In 6 unrelated patients with developmental delay with or without epilepsy (DEVEP; 620540), Syrbe et al. (2017) identified de novo heterozygous mutations in the SPTAN1 gene (see, e.g., 182810.0016-182810.0017). There were 4 missense mutations and 2 in-frame deletions. Fibroblasts derived from 2 patients did not show abnormal SPTAN1 aggregation, and alpha-2 spectrin was mainly present in the soluble fraction, similar to controls.
In 16 individuals (P11-P26) from 13 unrelated families (families 9 to 21) with DEVEP, Morsy et al. (2023) identified heterozygous mutations in the SPTAN1 gene (see, e.g., 182810.0018). The patients were ascertained through international collaborative efforts, including the GeneMatcher Program, after genetic analysis identified the variants. Most of the variants occurred de novo. Most of the variants were nonsense or frameshift; in addition, there were 4 in-frame deletions and 2 missense variants. The mutations occurred throughout the gene, and all but 1 (R2204Q) occurred before the C-terminal alpha/beta dimerization domain. Functional studies of the variants and studies of patient cells were not performed.
Associations Pending Confirmation
For discussion of a possible association between biallelic variation in the SPTAN1 gene and autosomal recessive spastic paraplegia (see, e.g., SPG5A, 270800), see 182810.0010-182810.0012.
Xie et al. (2022) reported a 27-year-old Chinese woman, born of consanguineous parents, with complicated spastic paraplegia associated with a homozygous I1388V variant in the SPTAN1 gene identified through homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. The variant, which segregated with the disorder in the family, was not present in the gnomAD database. Of note, the woman also had 9 additional rare homozygous variants in 9 different genes. The patient had onset of motor symptoms at 12 years of age and became wheelchair-bound at 22. She also had learning difficulties, poor school performance, and mild intellectual disability, but no seizures. Brain imaging showed mild atrophy of the cerebellar vermis and enlarged fourth ventricle.
In general, C-terminal in-frame deletions and duplications in the SPTAN1 gene that affect the last 2 spectrin repeats (19 and 20) are highly linked to severe early-onset DEE5. These mutations are located within the alpha/beta spectrin dimerization domain, and some have been shown to cause abnormal spectrin aggregates, consistent with a dominant-negative effect. In contrast, nonsense or frameshift mutations are seen more frequently in patients with HMND11, presumably due to haploinsufficiency. Missense mutations or in-frame deletions that do not affect the last 2 spectrin repeats tend to result in spastic paraplegia or ataxia (SPG91), sometimes with additional neurologic features. These mutations involve positively charged arginine or lysine residues and are hypothesized to disrupt stabilizing electrostatic interactions (Van de Vondel et al., 2022). Missense, nonsense, or in-frame deletions that occur outside of and before the C-terminal alpha-beta dimerization domain tend to result in the less severe phenotype developmental delay with or without epilepsy (DEVEP) (Morsy et al., 2023). However, there are exceptions: some patients with DEE5 have missense mutations, rather than in-frame deletions or duplications, within the C terminus or outside of the C terminus, and some with DEVEP have mutations within the alpha/beta dimerization domain (see Syrbe et al., 2017; Morsy et al., 2023).
From a genetic screen of zebrafish mutants, Voas et al. (2007) identified a homozygous Sptan1-null mutant that had reduced the numbers of nodal sodium-channel clusters in myelinated axons of the peripheral and central nervous systems. The defects were apparent at 5 days post-fertilization, and the zebrafish died by 15 days post-fertilization due to failure to inflate their swim bladders. Ultrastructural studies showed that myelin formed in the posterior lateral line nerve and in the ventral spinal cord in the mutant zebrafish, but that the node was abnormally long. Sptan1 was found to function autonomously in neurons and was enriched at nodes and paranodes in wildtype zebrafish. The results provided functional evidence that Sptan1 in the axonal cytoskeleton is essential for stabilizing nascent sodium-channel clusters and assembling the mature node of Ranvier.
In a Japanese girl with developmental and epileptic encephalopathy-5 (DEE5; 613477), who had a clinical diagnosis of West syndrome, Saitsu et al. (2010) identified a de novo heterozygous 3-bp in-frame deletion (c.6619_6621delGAG) in exon 50 of the SPTAN1 gene, resulting in a deletion of glu2207 (Glu2207del) in the continuous helix region between the last 2 spectrin repeats. The deletion was not found in 500 control Japanese alleles. In vitro functional expression studies showed that the mutant protein could form a heterodimer with spectrin beta-II (SPTBN1; 182790), but that the heterodimer was thermally unstable. Transient expression of the mutant SPTAN1 protein in mouse cortical neurons showed that the mutant protein formed aggregates with SPTNB1 and SPTBN2 (604985) in cell bodies and axons. Further studies showed that the aggregates disturbed the normal clustering of ankyrin-G (ANK3; 600465) at the axon initiation segment, and appeared to cause a depolarizing shift in the action potential. The overall findings suggested a dominant-negative effect. The patient had onset of intractable seizures at age 3 months and showed profound mental retardation, poor visual attention, lack of speech development, and spastic quadriplegia. Brain MRI showed diffuse hypomyelination and widespread brain atrophy affected the cortex, corpus callosum, brainstem, and cerebellum.
In an 8-month-old Slovenian girl with DEE5, who had a clinical diagnosis of West syndrome, Writzl et al. (2012) identified a de novo heterozygous 3-bp deletion (c.6619_6621delGAG) in the SPTAN1 gene. Functional studies were not performed.
In 2 unrelated patients (P6 and P7) with DEE5, Syrbe et al. (2017) identified a de novo heterozygous Glu2207del mutation in the SPTAN1 gene. Patient fibroblasts showed abnormal alpha-2/beta-2 spectrin aggregations.
In a 20-year-old African female (P29) with DEE5, Morsy et al. (2023) identified a de novo heterozygous Glu2207del mutation in the SPTAN1 gene. Patient fibroblasts showed decreased protein expression. Immunofluorescent studies showed intense localized irregular aggregation of SPTAN1 in the plasma membrane that was not observed in control cells.
In a Japanese boy with developmental and epileptic encephalopathy-5 (DEE5; 613477), who had a clinical diagnosis of West syndrome, Saitsu et al. (2010) identified a de novo heterozygous 6-bp in-frame duplication (nucleotides 6923-6928) in exon 53 of the SPTAN1 gene, resulting in the duplication of arg2308 and met2309 (Arg2308_Met2309dup) within the last spectrin repeat. The duplication was not found in 500 control Japanese alleles. Transient expression of the mutant SPTAN1 protein in mouse cortical neurons showed that the mutant protein formed aggregates with SPTNB1 and SPTBN2 in cell bodies and axons. Further studies showed that the aggregates disturbed the normal clustering of ankyrin-G at the axon initiation segment, and appeared to cause a depolarizing shift in the action potential. The mutant protein could form a heterodimer with SPTBN1, but the heterodimer was thermally unstable. The findings suggested a dominant-negative effect. The patient had onset of intractable seizures at age 3 months and showed profound mental retardation, poor visual attention, lack of speech development, and spastic quadriplegia. Brain MRI showed diffuse hypomyelination and widespread brain atrophy affected the cortex, corpus callosum, brainstem, and cerebellum.
In an 11-year-old French Canadian boy with developmental and epileptic encephalopathy-5 (DEE5; 613477), Hamdan et al. (2012) identified a de novo heterozygous 3-bp in-frame deletion (6605_6607) in the SPTAN1 gene, resulting in the deletion of amino acid gln2202 (Gln2202del) in the C-terminal domain required for alpha/beta spectrin subunit heterodimer formation. In vitro expression of the mutation in primary mouse cortical neurons caused formation of spectrin aggregates in about 20% of cells. In contrast, expression of the mutation in mouse neuroblastoma (N2A) cells showed localization of the protein at the cell periphery without the formation of aggregates, similar to wildtype. Although the patient did not present with early infantile spasms, he had febrile seizures at age 16 months and later developed mild generalized epilepsy and severe intellectual disability. Brain MRI showed severe atrophy of the cerebellum and mild atrophy of the brainstem, without any hypomyelination or other structural defects. Overall, the phenotype in this patient was less severe than that of the patients reported by Saitsu et al. (2010).
This variant is classified as a variant of unknown significance because its contribution to nonsyndromic intellectual disability has not been confirmed.
In a 9-year-old French Canadian boy with nonsyndromic mild intellectual disability, Hamdan et al. (2012) identified a de novo heterozygous 1697G-C transversion in the SPTAN1 gene, resulting in an arg566-to-pro (R566P) substitution in a well-conserved residue in the N-terminal domain. The mutation was not found in 190 French Canadian controls. The patient also had attention deficit with hyperactivity, but no dysmorphic features and no brain abnormalities on CT scan. The patient had a sister with nonsyndromic intellectual disability who did not carry the R566P mutation. In vitro expression of the R566P mutation in mouse neuroblastoma (N2A) cells induced large aggregates in 86% of cells. These mutant alpha-II spectrin aggregates colocalized with endogenous beta-II-spectrin subunits, but not with beta-III-spectrin subunits. In contrast, expression of R566P in primary mouse cortical neurons did not result in significant aggregate formation. Hamdan et al. (2012) concluded that the R566P mutation may not be responsible for the patient's phenotype.
In a 12-month-old Japanese boy with developmental and epileptic encephalopathy-5 (DEE5; 613477) who had a clinical diagnosis of West syndrome, Nonoda et al. (2013) identified a de novo heterozygous 9-bp duplication (c.6908_6916dup) in the SPTAN1 gene, resulting in a 3-residue duplication (Asp2303_Leu2305dup) in the last spectrin repeat. The mutation was not found in 250 Japanese control individuals. Functional studies of the variant were not performed. The patient had onset of epileptic spasms at age 3 months.
In 3 unrelated patients (P10, P11, and P12) with DEE5 and West syndrome, Syrbe et al. (2017) identified a de novo heterozygous c.6908_6916dup mutation in the SPTAN1 gene. Fibroblasts from P10 showed abnormal aggregation of alpha-2 spectrin that colocalized with beta-2 spectrin and clustered near the plasma membrane.
In 6 members of a 3-generation family (family A) with autosomal dominant distal hereditary motor neuronopathy-11 (HMND11; 620528), Beijer et al. (2019) identified a heterozygous c.415C-T transition (c.415C-T, NM_003127) in the SPTAN1 gene, resulting in an arg139-to-ter (R139X) substitution in the N-terminal spectrin repeat domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the ExAC or gnomAD databases. Western blot analysis of patient lymphoblasts showed decreased SPTAN1 protein levels at about 60 to 80% compared to noncarriers due to nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency. Both patient cells and control cells showed mostly soluble SPTAN1, although there was a clear insoluble fraction in both cell lines. Patient fibroblasts showed normal localization of SPTAN1 in small puncta throughout the cytoplasm with no aggregates, similar to controls.
In 4 members of a 3-generation family (family B) with autosomal dominant distal hereditary motor neuronopathy-11 (HMND11; 620528), Beijer et al. (2019) identified a heterozygous c.4615C-T transition (c.4615C-T, NM_003127) in the SPTAN1 gene, resulting in a gln1539-to-ter (Q1539X) substitution in a spectrin repeat domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There was 1 unaffected mutation carrier, suggesting incomplete penetrance. The mutation was not present in the ExAC or gnomAD databases. Western blot analysis of patient lymphoblasts showed decreased SPTAN1 protein levels at about 60 to 80% compared to noncarriers due to nonsense-mediated mRNA decay. The findings were consistent with haploinsufficiency. Both patient cells and control cells showed mostly soluble SPTAN1, although there was a clear insoluble fraction in both cell lines. Patient fibroblasts showed normal localization of SPTAN1 in small puncta throughout the cytoplasm with no aggregates, similar to controls.
In a 20-year-old man with autosomal dominant distal hereditary motor neuronopathy-11 (HMND11; 620528), Ylikallio et al. (2020) identified a de novo heterozygous 1-bp deletion (c.6367del, NM_001130438.3) in exon 49 of the SPTAN1 gene, predicted to result in a frameshift and premature termination (Val2123CysfsTer45). The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD, Exome Sequencing Project, or 1000 Genomes Project databases. Patient cells were not available for study, but the mutation was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency. The patient had onset of motor symptoms beginning in early childhood, which progressed to a distal predominantly motor neuropathy by age 13 years. Electrophysiologic studies were consistent with an axonal sensorimotor polyneuropathy, although clinical sensory defects were not noted. He also had language delay, learning disabilities, dyslexia, and difficulties in executive function, but was able to attend a normal school with special education. Accelerated growth since childhood and a marfanoid habitus were also present.
In a 21-year-old Han Chinese woman with autosomal dominant distal hereditary motor neuronopathy-11 (HMND11; 620528), Dong et al. (2021) identified a de novo heterozygous c.6781C-T transition (c.6781C-T, NM_001130438) in the SPTAN1 gene, resulting in an arg2261-to-ter (R2261X) substitution in the last spectrin repeat in the C-terminal region critical for the formation of alpha/beta spectrin heterotetramers. The mutation, which was found by whole-exome sequencing, was not present in the ExAC, dbSNP, 1000 Genomes Project, or gnomAD databases. Studies of HEK293 cells transfected with the mutation showed that it triggered nonsense-mediated mRNA decay, consistent with haploinsufficiency. The patient had onset of a motor axonal neuropathy affecting the lower limbs at age 12 years, which progressed to involve the distal upper limbs and hands by age 18. Electrophysiologic studies showed a motor axonal neuropathy with normal sensory results. Sensory examination and brain imaging were normal, and cognitive defects were not reported.
This variant is classified as a variant of unknown significance because its contribution to autosomal recessive spastic paraplegia (see, e.g., SPG5A, 270800) has not been confirmed.
In 2 unrelated men (patient A who was 41 years old and patient B who was 48 years old) with autosomal recessive spastic paraplegia, Leveille et al. (2019) identified compound heterozygous missense variants in the SPTAN1 gene. Both carried a c.2572G-T transversion (c.2572G-T, NM_003127), resulting in an ala858-to-ser (A858S) substitution at a conserved residue in the eighth spectrin repeat on 1 allele. Patient A carried a c.4283C-G transversion, resulting in an ala1428-to-gly (A1428G; 182810.0011) substitution at a conserved residue in the 12th spectrin repeat on the other allele, whereas patient B carried a c.6990G-C transversion, resulting in a met2330-to-ile (M2330I; 182810.0012) substitution at a conserved residue in the first EF hand on the other allele. The EF hand is a calcium-binding domain that regulates contact with F-actin. The variants were found by whole-exome sequencing and confirmed by Sanger sequencing. Familial segregation studies in patient A showed that each unaffected parent was a carrier for 1 of the variants; parental DNA was not available for segregation studies for patient B. All 3 variants were present at a low frequency in heterozygous state in the gnomAD database (1.77 x 10(-5) for A858S, 5.586 x 10(-4) for A1428G, and 1.193 x 10(-5) for M2330I). Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that the substitutions may adversely affect protein conformation or domain interactions. The patients had onset at 33 and 15 years, respectively, of a slowly progressive disorder characterized by spasticity of the lower limbs and hyperreflexia of the upper limbs. Patient A had abnormal bladder function and extraocular movement abnormalities, whereas patient B had mild sensory abnormalities. The phenotype was generally mild, and both patients were ambulatory. Neither had seizures or intellectual disability, and brain imaging was normal. The patients were ascertained from a large cohort of 383 patients from 289 Canadian families with hereditary spastic paraplegia who underwent exome sequencing; SPTAN1 variants thus accounted for only 0.5% of this cohort (2 of 383 patients), indicating that, if causative, they are very rare.
This variant is classified as a variant of unknown significance because its contribution to autosomal recessive spastic paraplegia (see, e.g., SPG5A, 270800) has not been confirmed.
For discussion of the c.4283C-G transversion (c.4283C-G, NM_003127) in the SPTAN1 gene, resulting in an ala1428-to-gly (A1428G) substitution, that was found in compound heterozygous state in a patient (patient A) with autosomal recessive spastic paraplegia by Leveille et al. (2019), see 182810.0010.
This variant is classified as a variant of unknown significance because its contribution to autosomal recessive spastic paraplegia (see, e.g., SPG5A, 270800) has not been confirmed.
For discussion of the c.6990G-C transversion (c.6990G-C, NM_003127) in the SPTAN1 gene, resulting in a met2330-to-ile (M2330I) substitution, that was found in compound heterozygous state in a patient (patient B) with autosomal recessive spastic paraplegia by Leveille et al. (2019), see 182810.0010.
In affected members of 7 unrelated families (families E-K) with autosomal dominant spastic paraplegia-91 with or without cerebellar ataxia (SPG91; 620538), Van de Vondel et al. (2022) identified a heterozygous c.55C-T transition (c.55C-T, NM_001130438.2) in the SPTAN1 gene, resulting in an arg19-to-trp (R19W) substitution in the N-terminal domain. The mutation, which was found by whole-exome or whole-genome sequencing, segregated with the disorder in the families from whom parental DNA was available. The mutation in at least 1 case (family F) was demonstrated to occur de novo. One large family (family K) contained 10 affected individuals spanning 3 generations who were found to carry the mutation. The mutation was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the mutation would result in destabilization of electrostatic interactions at the heterotetramerization site. Most patients had a relatively pure form of spastic paraplegia, although there was phenotypic variability, even within a family. Additional more variable features observed in some patients included cerebellar ataxia, pes cavus, sensorimotor peripheral neuropathy, and optic neuropathy. None had intellectual disability, and only 2 patients had seizures.
Morsy et al. (2023) reported 6 patients from 4 unrelated families (families 1-4) with SPG91 associated with a heterozygous R19W mutation. The mutation in family 2 (3 affected individuals) showed autosomal dominant transmission. The mutation in the patient from family 4 occurred de novo; the single patients in families 1 and 3 had sporadic disease, but the unaffected parents were not sequenced. Fibroblasts derived from 1 patient showed normal protein levels. Immunofluorescent studies showed intense irregular expression and aggregation of SPTAN1 throughout the patient cells that was not observed in control cells.
Spastic Paraplegia 91, Autosomal Dominant, with or without Cerebellar Ataxia
In 4 unrelated patients (families A-D) with autosomal dominant spastic paraplegia-91 with or without cerebellar ataxia (SPG91; 620538), Van de Vondel et al. (2022) identified a heterozygous 3-bp in-frame deletion (c.6247_6249delAAG, NM_001130438.2) in the SPTAN1 gene, resulting in the deletion of residue Lys2083 (K2083del). None of the patients had a family history of the disorder, and the mutations were demonstrated to have occurred de novo in 2 patients. The mutation was not present in gnomAD. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggested that the mutation would result in destabilization of electrostatic interactions at the heterotetramerization site. The most predominant phenotype in these patients was cerebellar ataxia associated with cerebellar atrophy; 3 patients had impaired intellectual development.
Developmental and Epileptic Encephalopathy 5
In a 16-year-old girl (P27) with developmental and epileptic encephalopathy-5 (DEE5; 613477), Morsy et al. (2023) identified a heterozygous Lys2083del mutation in the SPTAN1 gene. The patient had onset of absence seizures at 2 months of age. She showed impaired intellectual development, learning disability, speech and motor delay, and strabismus. She was also noted to have ataxia.
In a 3-year-old girl (P9) with developmental and epileptic encephalopathy-5 (DEE5; 613477), Syrbe et al. (2017) identified a de novo heterozygous c.6811G-A transition (c.6811G-A, NM_001130438) in exon 53 of the SPTAN1 gene, resulting in a glu2271-to-lys (E2271K) substitution at a highly conserved residue in the last spectrin repeat domain (20) just before the EF-hand domain in the alpha/beta heterodimerization domain at the C terminus. Morsy et al. (2023) also identified a de novo heterozygous E2271K mutation in the SPTAN1 gene in a 12-year-old boy (P28) with DEE5. They also noted that mutation occurred in the alpha/beta heterodimerization domain, likely disrupting this interaction. Both patients were severely affected and had cerebellar atrophy, delayed myelination, and thin corpus callosum on brain imaging. P28 had retinal dystrophy. Functional studies of the variant and studies of patient cells were not performed. This mutation is a rare missense mutation in the C terminus of the gene associated with DEE5. Most DEE5-related mutations occur at the C terminus, but cause in-frame duplications or deletions.
In an 18-year-old male (P2) with developmental delay and epilepsy (DEVEP; 620540), Syrbe et al. (2017) identified a de novo heterozygous c.917C-T transition (c.917C-T, NM_001130438) in the SPTAN1 gene, resulting in an ala306-to-val (A306V) substitution at a highly conserved residue in the third spectrin repeat near the N-terminal domain. Patient fibroblasts did not show abnormal SPTAN1 aggregation, and alpha-2 spectrin was mainly present in the soluble fraction, similar to controls. The patient had onset of myoclonic and atonic seizures at 2 years of age that were partially controlled by medication. He had moderate intellectual disability and walked normally. Brain imaging was normal.
In a 19-year-old male (P15) with developmental delay and epilepsy (DEVEP; 620540), Syrbe et al. (2017) identified a de novo heterozygous 9-bp in-frame deletion (c.6908_6916del, NM_001130438) in the SPTAN1 gene, resulting in the deletion of 3 conserved residues (Asp2303_Leu2305del) in the last spectrin repeat (repeat 20) in the C-terminal domain. Patient fibroblasts did not show abnormal SPTAN1 aggregation, and alpha-2 spectrin was mainly present in the soluble fraction, similar to controls. This mutation is similar to another SPTAN1 mutation that causes a duplication of the same nucleotides (Asp2303_Leu2305dup; 182810.0005) found in patients with developmental and epileptic encephalopathy-5 (DEE5; 613477). The patient with the Asp2303_Leu2305del mutation had onset of febrile seizures at 17 months of age followed by focal seizures at 5 years of age. He became seizure-free on medication. He had moderate intellectual disability and ADHD; brain imaging was normal.
In a 9-year-old boy (P22) with developmental delay and epilepsy (DEVEP; 620540), Morsy et al. (2023) identified a de novo heterozygous c.4390C-T transition (c.4390C-T, NM_001130438.3) in exon 34 of the SPTAN1 gene, resulting in an arg1464-to-trp (R1464W) substitution at a conserved residue in spectrin repeat 13. Functional studies of the variant and studies of patient cells were not performed, but molecular modeling predicted that the mutation would result in a decrease in molecule flexibility.
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