Alternative titles; symbols
HGNC Approved Gene Symbol: TECPR2
Cytogenetic location: 14q32.31 Genomic coordinates (GRCh38) : 14:102,362,941-102,502,477 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.31 | Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay | 615031 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1997) cloned TECPR2, which they designated KIAA0329. The deduced 1,411-amino acid protein shares significant similarity with an Aspergillus nidulans SepB, a protein involved in cell division. RT-PCR analysis detected highest TECPR2 expression in kidney, followed by ovary and testis. SDS-PAGE detected in vitro translated TECPR2 at an apparent molecular mass above 100 kD.
By radiation hybrid analysis, Nagase et al. (1997) mapped the TECPR2 gene to chromosome 14.
Hartz (2012) mapped the TECPR2 gene to chromosome 14q32.31 based on an alignment of the TECPR2 sequence (GenBank AB002327) with the genomic sequence (GRCh37).
In affected members of 3 Jewish Bukharian families with hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9; 615031), originally diagnosed with autosomal recessive spastic paraplegia-49 (SPG49), Oz-Levi et al. (2012) identified a homozygous frameshift mutation in the TECPR2 gene (c.3416delT; 615000.0001). The mutation was found by exome sequencing and segregated with the disorder in each family. The phenotype was characterized by delayed motor development, spastic paraparesis, gastroesophageal reflux, and recurrent apneic episodes. The patients also had impaired intellectual development and mild dysmorphic features. Skin fibroblasts from an affected individual showed impaired expression of the autophagocytic proteins SQSTM1 (601530) and MAP1LC3B (609604) in response to various conditions that should have increased the levels of these proteins. The findings suggested that TECPR2 mutations cause impairment of the intracellular autophagy pathway, with attenuation of delivery of targeted proteins to the lysosome.
In 3 unrelated patients of Ashkenazi or Ashkenazi/Turkish descent with HSAN9, Heimer et al. (2016) identified homozygous or compound heterozygous mutations in the TECPR2 gene (615000.0001-615000.0003). The mutations, which were identified by whole-exome or Sanger sequencing, segregated with disease in each family.
In a 5-year-old girl with HSAN9, Patwari et al. (2020) identified compound heterozygous mutations the TECPR2 gene (615000.0004; 615000.0005).
In a 16-year-old Italian girl with HSAN9, Covone et al. (2016) identified compound heterozygosity for 2 missense mutations in the TECPR2 gene (NM_014844.3): c.898G-A (G300R) and c.2708C-T (T903M). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The patient also had a mutation in the SPG7 gene (602783), which was present in her unaffected father. Functional studies were not performed.
In 17 patients in 15 families segregating HSAN9 who were recruited through Gene Matcher or personal communication, Neuser et al. (2021) identified homozygous or compound heterozygous mutations in the TECPR2 gene (see, e.g., 615000.0001; 615000.0002; 615000.0006-615000.0007). The mutations were identified by whole-exome sequencing, genetic panel testing, or targeted Sanger sequencing.
Tamim-Yecheskel et al. (2021) used CRISPR editing to generate a Tecpr2 knockout mouse. Western blot analysis in mouse embryonic fibroblasts showed absence of Tepcr2 protein expression. The knockout mice displayed sensory and gait defects, including abnormalities in motor coordination and hypersensitivity to thermal stimuli. Brain MRIs of 4- to 5-month-old knockout mice demonstrated signal abnormalities indicating inflammation and degeneration in several brain regions as well as abnormalities in gray and white matter of motor and sensory tracts. Studies in neuronal tissue of the knockout mice showed an overall decrease of neurofilament and a neuroaxonal dystrophy with axonal swelling in the medulla oblongata. In brainstem sections of 9-month-old knockout mice, autophagosomes were seen, and immunoblot analysis of the autophagosomes showed enrichment of MAP1LC3B (609604) and SQSTM1 (601530) but not of the lysosomal marker LAMP2 (309060). Tamim-Yecheskel et al. (2021) concluded that these findings indicate that Tecpr2 plays a role in autophagy and autophagosome consumption.
In affected members of 3 Jewish Bukharian families with hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9; 615031), who were originally diagnosed with autosomal recessive spastic paraplegia-49 (SPG49), Oz-Levi et al. (2012) identified a homozygous 1-bp deletion (c.3416delT) in exon 16 of the TECPR2 gene, resulting in a frameshift and premature termination (Leu1139ArgfsTer75). The mutation was found by exome sequencing and segregated with the disorder in each family. The mutation was not present in 2,007 non-Bukharian controls, but was found in 4 of 300 Jewish Bukharian control chromosomes, yielding an allele frequency of 0.013 in that ethnic group. In vitro cellular expression assays indicated that the mutant protein was degraded by the proteosome.
In a patient with HSAN9 (patient 3), Heimer et al. (2016) identified compound heterozygosity for 2 mutations in the TECPR2 gene: c.3416delT (c.3416delT, NM_001172631) and a 1-bp deletion (c.1319delT; 615000.0002) in exon 8, predicted to result in a frameshift and premature termination (Leu440ArgfsTer19). The mutations were identified by Sanger sequencing of the TECPR2 gene, and both parents were shown to be mutation carriers.
In 2 patients with HSAN9, Neuser et al. (2021) identified homozygosity for the c.3416delT mutation in the TECPR2 gene. They noted that the minor allele frequency of the c.3416delT variant was 2/247,472 in only heterozygous state in the gnomAD database.
In an Ashkenazi Jewish patient (patient 2) with hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9; 615031), Heimer et al. (2016) identified homozygosity for 1-bp deletion (c.1319delT, NM_001172631) in exon 8 of the TECPR2 gene, predicted to result in a frameshift and premature termination (Leu440ArgfsTer19). The mutation was not present in the NHLBI Exome Sequencing Project and dbSNP (build 38) databases or in an in-house database of 240 exomes; it was identified in heterozygous state in 3 of 900 exomes in the Hadassah in-house database and in 9 of 2,000 exomes from the Ashkenazi exome project. In another Ashkenazi Jewish patient (patient 1), Heimer et al. (2016) identified c.1319delT in compound heterozygous state with a c.566C-T transition in exon 3, resulting in a thr189-to-ile (T189I; 615000.0003) substitution. In patient 3, of Ashkenazi and Turkish descent, c.1319delT was found in compound heterozygous state with a previously identified c.3416delT mutation (615000.0001). The mutations segregated with the phenotype in all 3 families.
In 5 patients with HSAN9, Neuser et al. (2021) identified the c.1319del founder mutation in the TECPR2 gene, in homozygosity in 4 and in compound heterozygosity in 1. They noted that the minor allele frequency of the c.1319del variant was 37/275,698 in only heterozygous state in the gnomAD database.
For discussion of the c.566C-T transition (c.566C-T, NM_001172631) in exon 3 of the TECPR2 gene, resulting in a thr189-to-ile (T189I) substitution, that was found in compound heterozygous state in a patient with hereditary sensory and autonomic neuropathy type IX with developmental delay (HSAN9; 615031) by Heimer et al. (2016), see 615000.0002.
In a patient with hereditary sensory and autonomic type IX with developmental delay (HSAN9; 615031), Patwari et al. (2020) identified compound heterozygous mutations in the TECPR2 gene: a 1-bp deletion (c.774delA), predicted to result in a frameshift and premature termination (Asp259MetfsTer44) and a 5-bp deletion (c.1028_1032delAAGGA; 615000.0005), predicted to result in a frameshift and premature termination (Lys343ArgfsTer2). The mutations were identified by whole-exome sequencing. Functional studies were not performed.
For discussion of the 5-bp deletion (c.1028_1032delAAGGA) in the TECPR2 gene, predicted to result in a frameshift and premature termination (Lys343ArgfsTer2), that was found in compound heterozygous state in a patient with hereditary sensory and autonomic type IX with developmental delay (HSAN9; 615031) by Patwari et al. (2020), see 615000.0004.
In 2 Pakistani sibs (patients 14 and 15), born to consanguineous parents with hereditary sensory and autonomic type IX with developmental delay (HSAN9; 615031), Neuser et al. (2021) identified homozygosity for a c.4103G-A transition (c.4103G-A, NM_014844.4) in exon 20 of the TECPR2 gene, resulting in a trp1368-to-ter (W1368X) substitution. The mutation was identified by whole-exome sequencing. Functional studies were not performed.
In 2 Saudi Arabian sibs (patients 7 and 8), born to consanguineous parents, with hereditary sensory and autonomic type IX with developmental delay (HSAN9; 615031), Neuser et al. (2021) identified homozygosity for a c.2998G-T transversion (c.2998G-T, NM_014844.4) in the TECPR2 gene, resulting in an asp1000-to-tyr (D1000Y) substitution at a conserved residue in the C terminus. The mutation was identified by whole-exome sequencing. Functional studies were not performed.
Covone, A. E., Fiorillo, C., Acquaviva, M., Trucco, F., Morana, G., Ravazzolo, M. G., Minetti, C. WES in a family trio suggests involvement of TECPR2 in a complex form of progressive motor neuron disease. Clin. Genet. 90: 182-185, 2016. [PubMed: 27406698] [Full Text: https://doi.org/10.1111/cge.12730]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/20/2012.
Heimer, G., Oz-Levi, D., Eyal, E., Edvardson, S., Nissenkorn, A., Ruzzo, E. K., Szeinberg, A., Maayan, C., Mai-Zahav, M., Efrati, O., Pras, E., Reznik-Wolf, H., Lancet, D., Goldstein, D. B., Anikster, Y., Shalev, S. A., Elpeleg, O., Ben Zeev, B. TECPR2 mutations cause a new subtype of familial dysautonomia like hereditary sensory autonomic neuropathy with intellectual disability. Europ. J. Paediat. Neurol. 20: 69-79, 2016. [PubMed: 26542466] [Full Text: https://doi.org/10.1016/j.ejpn.2015.10.003]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Neuser, S., Brechmann, B., Heimer, G., Brosse, I., Schubert, S., O'Grady, L., Zech, M., Srivastava, S., Sweetser, D. A., Dincer, Y., Mall, V., Winkelmann, J., and 38 others. Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability. Hum. Mutat. 42: 762-776, 2021. [PubMed: 33847017] [Full Text: https://doi.org/10.1002/humu.24206]
Oz-Levi, D., Ben-Zeev, B., Ruzzo, E. K., Hitomi, Y., Gelman, A., Pelak, K., Anikster, Y., Reznik-Wolf, H., Bar-Joseph, I., Olender, T., Alkelai, A., Weiss, M., Ben-Asher, E., Ge, D., Shianna, K. V., Elazar, Z., Goldstein, D. B., Pras, E., Lancet, D. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am. J. Hum. Genet. 91: 1065-1072, 2012. [PubMed: 23176824] [Full Text: https://doi.org/10.1016/j.ajhg.2012.09.015]
Patwari, P. P., Wolfe, L. F., Sharma, G. D., Berry-Kravis, E. TECPR2 mutation-associated respiratory dysregulation: more than central apnea. J. Clin. Sleep Med. 16: 977-982, 2020. [PubMed: 32209221] [Full Text: https://doi.org/10.5664/jcsm.8434]
Tamim-Yecheskel, B.-C., Fraiberg, M., Kokabi, K., Freud, S., Shatz, O., Marvaldi, L., Subic, N., Brenner, O., Tsoory, M., Eilam-Altstadter, R., Biton, I., Savidor, A., Dezorella, N., Heimer, G., Behrends, C., Ben-Zeev, B., Elazar, Z. A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophy associated with autophagosome accumulation. Autophagy 17: 3082-3095, 2021. [PubMed: 33218264] [Full Text: https://doi.org/10.1080/15548627.2020.1852724]