Alternative titles; symbols
HGNC Approved Gene Symbol: SKIC3
Cytogenetic location: 5q15 Genomic coordinates (GRCh38) : 5:95,463,894-95,554,977 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q15 | Trichohepatoenteric syndrome 1 | 222470 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated human brain cDNA library, Nagase et al. (1997) cloned TTC37, which they designated KIAA0372. The deduced protein contains 1,564 amino acids. RT-PCR analysis detected high expression in placenta and low expression in kidney and ovary. Little to no expression was detected in all other tissues examined.
Fabre et al. (2011) assessed quantitative expression of TTC37 in a panel of 48 different tissues and found that TTC37 is widely expressed, with the highest levels observed in vascular tissues, lymph node, pituitary, lung, and intestine. They found no expression in liver.
By radiation hybrid analysis, Nagase et al. (1997) mapped the TTC37 gene to chromosome 5.
Amberger (2012) mapped the TTC37 gene (SKIC3) to chromosome 5q15 based on an alignment of the TTC37 sequence (GenBank AB002370) with the genomic sequence (GRCh37).
In 12 children from 11 unrelated families with trichohepatoenteric syndrome mapping to chromosome 5q14.3-q21.2 (THES1; 222470), Hartley et al. (2010) identified homozygosity or compound heterozygosity for 9 different mutations in the candidate gene TTC37 (see, e.g., 614589.0001-614589.0005). Preliminary studies in 5 patients of enterocyte brush-border ion transporter proteins, including NHE2 (SLC9A2; 600530), NHE3 (SLC9A3; 182307), NIS (SLC5A5; 601843), AQP7 (602974), and H/K ATPase (see ATP4A, 137216), demonstrated reduced expression or mislocalization compared to controls. Hartley et al. (2010) suggested that the multisystem effect of TTC37 mutations might be due to abnormal stability and/or intracellular localization of TTC37 target proteins.
Fabre et al. (2011) analyzed the TTC37 gene in 12 THES patients from 11 families and identified homozygosity or compound heterozygosity for 11 different mutations in 9 of the patients (see, e.g., 614589.0006-614589.0008).
In a 12-year-old Saudi girl with THES and numerous cafe-au-lait spots below the waist, Monies et al. (2015) screened a gastrointestinal disease-associated gene panel and identified homozygosity for a nonsense mutation in the TTC37 gene (Q1368X; 614589.0009) that segregated with disease in the family.
In 2 brothers from a consanguineous family of Somalian descent who died in infancy with THES, Kinnear et al. (2017) identified homozygosity for a missense mutation in the TTC37 gene (R1503C; 614589.0010). The mutation was confirmed by Sanger sequencing, which also showed that their parents and sister were heterozygous for the variant. The authors stated that these were the first reported Somali patients with THES, and noted that THES had not been previously diagnosed in South Africa, where consanguinity was uncommon.
In 4 children with trichohepatoenteric syndrome (THES1; 222470), including 2 sisters from an Indian family and 2 boys from 2 unrelated consanguineous Pakistani families, Hartley et al. (2010) identified homozygosity for a 2808G-A transition in exon 28 of the TTC37 (SKIC3) gene, resulting in a trp936-to-ter (W936X) substitution. SNP haplotypes in the affected individuals were identical over a 974-kb region containing TTC37, from SNP rs255375 to SNP rs34897, consistent with a founder mutation. The mutation segregated with disease in each family and was not found in at least 350 ethnically matched South Asian and Caucasian control chromosomes. All 4 children had intrauterine growth retardation, villous atrophy on jejunal biopsies, and trichorrhexis nodosa. The Indian sisters, who both exhibited thrombocytosis and large platelets, died at 6 months of age; 1 sib also had a ventricular septal defect. The Pakistani boys had no platelet abnormalities or cardiac defects; 1 died at 8 years of age, whereas the other was alive at 1 year of age. Analysis of enterocyte brush-border ion transporter proteins in 1 of the patients demonstrated that apical expression of AQP7 (602974) was absent, suggesting that TTC37 may regulate expression of AQP7.
In an 11-year-old Pakistani girl and an unrelated 3.5-year-old Pakistani boy with trichohepatoenteric syndrome-1 (THES1; 222470), both from consanguineous families, Hartley et al. (2010) identified homozygosity for a G-A transition at -2 in intron 28 (2779-2G-A) in the TTC37 (SKIC3) gene, predicted to cause skipping of exon 29 and premature termination. The mutation segregated with disease in both families and was not found in at least 350 ethnically matched South Asian and Caucasian control chromosomes. Both children had intrauterine growth retardation, characteristic facial dysmorphology, villous atrophy on jejunal biopsies, trichorrhexis nodosa, and low immunoglobulins, and both exhibited developmental delay. In addition, the girl had mild aortic insufficiency and the boy had peripheral pulmonary stenosis. Analysis of enterocyte brush-border ion transporter proteins in the 2 patients demonstrated that apical expression of H/K ATPase (see ATP4A, 137216) was reduced and that of AQP7 (602974) was absent, and there was mislocalization of NHE2 (SLC9A2; 600530), NHE3 (SLC9A3; 182307), and NIS (SLC5A5; 601843) compared to controls, suggesting that the multisystem effect of TTC37 mutations might be due to abnormal stability and/or intracellular localization of TTC37 target proteins.
In a 2.5-year-old girl from a consanguineous Kurdish family with trichohepatoenteric syndrome-1 (THES1; 222470), Hartley et al. (2010) identified homozygosity for a 1-bp deletion in intron 17 (1632+1delG) of the TTC37 (SKIC3) gene, producing a frameshift predicted to result in a premature termination codon. The mutation segregated with disease in the family and was not found in at least 350 ethnically matched South Asian and Caucasian control chromosomes. Analysis of enterocyte brush-border ion transporter proteins in the patient demonstrated that apical expression of H/K ATPase (see ATP4A, 137216) was reduced and that of AQP7 (602974) was absent.
In a 13-year-old Italian girl with trichohepatoenteric syndrome-1 (THES1; 222470), Hartley et al. (2010) identified compound heterozygosity for a 439C-T transition in exon 8 of the TTC37 (SKIC3) gene, resulting in a gln147-to-ter (Q147X) substitution, and a 2251C-T transition in exon 21, resulting in a gln751-to-ter (Q751X; 614589.0005) substitution. The mutations segregated with disease in the family and were not found in at least 350 ethnically matched South Asian and Caucasian control chromosomes. Features in this patient included intrauterine growth retardation, characteristic facial dysmorphology, villous atrophy on jejunal biopsy, trichorrhexis nodosa, diffuse hypopigmentation of the skin, low immunoglobulins, aortic insufficiency, and developmental delay.
For discussion of the gln751-to-ter (Q751X) mutation in the TTC37 (SKIC3) gene that was found in compound heterozygous state in a patient with trichohepatoenteric syndrome-1 (THES1; 222470) by Hartley et al. (2010), see 614589.0004.
In a North African patient with trichohepatoenteric syndrome (THES1; 222470), Fabre et al. (2011) identified homozygosity for a G-C transversion in intron 23 (2515+1G-C) of the TTC37 (SKIC3) gene. Direct sequencing of RNA transcripts from lymphoblastoid cells revealed that the mutation caused a frameshift and creation of a premature termination codon. The mutation was found in heterozygosity in the unaffected parents.
In a French patient with trichohepatoenteric syndrome-1 (THES1; 222470), Fabre et al. (2011) identified compound heterozygosity for a 5-bp deletion in IVS24 (2577-7_-3delTTTTT) of the TTC37 (SKIC3) gene, and a G-C transversion in IVS42 (4620+1G-C; 614589.0008). Direct sequencing of RNA transcripts from lymphoblastoid cells revealed that the 2577-7_-3delTTTTT mutation caused skipping of exon 25, resulting in the deletion of 19 in-frame amino acids, whereas the 4620+1G-C mutation caused cryptic splice activation in exon 42, resulting in alternative splicing and the replacement of the 41 terminal amino acids by 61 others.
For discussion of the splice site mutation in the TTC37 (SKIC3) gene (4620+1G-C) that was found in compound heterozygous state in a patient with trichohepatoenteric syndrome-1 (THES1; 222470) by Fabre et al. (2011), see 614589.0007.
In a 12-year-old Saudi girl (family 2, II-9) with trichohepatoenteric syndrome and numerous cafe-au-lait spots on the skin below the waist (THES1; 222470), Monies et al. (2015) screened a gastrointestinal disease-associated gene panel and identified homozygosity for a c.4102C-T transition in exon 39 of the TTC37 gene, resulting in a gln1368-to-ter (Q1368X) substitution within the tetratricopeptide-like helical domain. The mutation segregated with disease in the family. Functional studies of the variant were not performed.
In 2 brothers from a consanguineous family of Somalian descent who died in infancy with trichohepatoenteric syndrome (THES1; 222470), Kinnear et al. (2017) identified homozygosity for a c.4507C-T transition (c.4507C-T, NM_014639) in exon 42 of the TTC37 gene, resulting in an arg1503-to-cys (R1503C) substitution at a highly conserved residue. The mutation was confirmed by Sanger sequencing, which also showed that their parents and sister were heterozygous for the variant. Functional studies of the variant were not performed.
Amberger, J. S. Personal Communication. Baltimore, Md. 4/24/2012.
Fabre, A., Martinez-Vinson, C., Roquelaure, B., Missirian, C., Andre, N., Breton, A., Lachaux, A., Odul, E., Colomb, V., Lemale, J., Cezard, J.-P., Goulet, O., Sarles, J., Levy, N., Badens, C. Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome. Hum. Mutat. 32: 277-281, 2011. [PubMed: 21120949] [Full Text: https://doi.org/10.1002/humu.21420]
Hartley, J. L., Zachos, N. C., Dawood, B., Donowitz, M., Forman, J., Pollitt, R. J., Morgan, N. V., Tee, L., Gissen, P., Kahr, W. H. A., Knisely, A. S., Watson, S., Chitayat, D., Booth, I. W., Protheroe, S., Murphy, S., De Vries, E., Kelly, D. A., Maher, E. R. Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy). Gastroenterology 138: 2388-2398, 2010. [PubMed: 20176027] [Full Text: https://doi.org/10.1053/j.gastro.2010.02.010]
Kinnear, C., Glanzmann, B., Banda, E., Schlechter, N., Durrheim, G., Neethling, A., Nel, E., Schoeman, M., Johnson, G., van Helden, P. D., Hoal, E. G., Esser, M., Urban, M., Moller, M. Exome sequencing identifies a novel TTC37 mutation in the first reported case of trichohepatoenteric syndrome (THE-S) in South Africa. BMC Med. Genet. 18: 26, 2017. [PubMed: 28292286] [Full Text: https://doi.org/10.1186/s12881-017-0388-5]
Monies, D. M., Rahbeeni, Z., Abouelhoda, M., Naim, E. A., Al-Younes, B., Meyer, B. F., Al-Mehaidib, A. Expanding phenotypic and allelic heterogeneity of tricho-hepato-enteric syndrome. J. Pediat. Gastroent. Nutr. 60: 352-356, 2015. [PubMed: 25714577] [Full Text: https://doi.org/10.1097/MPG.0000000000000627]
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]