Alternative titles; symbols
HGNC Approved Gene Symbol: MT-TS1
SNOMEDCT: 722203001;
The mitochondrial tRNA for serine (UCN) is encoded by nucleotides 7445-7516.
By screening for heteroplasmy by means of chemical cleavage of mismatch (CCM) and nucleotide sequencing in a family with MERRF (545000)/MELAS (540000) overlap syndrome, Nakamura et al. (1995) identified a heteroplasmic 7512T-C transition in the MTTS1 gene. The mutation disrupted a highly conserved basepair in the acceptor stem. The mutation was not found in any of 120 normal controls or in 43 patients with mitochondrial diseases. The proportion of the mutant mtDNA was 93% in muscle and 76% and 87% in the blood of the affected mother and daughter, respectively.
Jaksch et al. (1998) reported the same mutation in 2 patients with mitochondrial encephalopathy and cytochrome c oxidase deficiency (220110) associated with sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental retardation.
Reid et al. (1994) reported a novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness (500008). The deafness was progressive, postlingual, and involved high frequencies. The mutation was a T-to-C transition at nucleotide 7445 of the MTTS1 gene. Reid et al. (1994) used the antisense sequence as the reference in stating the nature of the mutation in this case. By convention, most researchers report mtDNA mutations by the standard sequence of Anderson et al. (1981), which is the sense strand for the majority of the open reading frames. Using this convention, the mutation in the MTTS1 gene described by Reid et al. (1994) should be given as 7445A-G instead of the complementary 7445T-C. (In fact, in a paper later in the same year, Reid et al. (1994) used the A-G terminology for this mutation.) The pedigree studied by Reid et al. (1994) was of Scottish maternal origin.
Fischel-Ghodsian et al. (1995) described deafness due to this mutation in a New Zealand pedigree. On more detailed clinical examination of the New Zealand family, Sevior et al. (1998) found that many relatives had palmoplantar keratoderma in addition to deafness (148350). Review of the literature demonstrated 3 other large families with presumed autosomal dominant inheritance of palmoplantar keratoderma and hearing loss. One of these families, a Japanese pedigree reported by Hatamochi et al. (1982) in which 5 members had deafness and palmoplantar keratoderma, had only maternal transmission. Analysis by Sevior et al. (1998) documented the same 7445A-G mitochondrial mutation that had previously been identified in the New Zealand and Scottish pedigrees. The mitochondrial sequence variants reported in the New Zealand and Scottish pedigrees were absent from the Japanese pedigree, which suggested that the 7445A-G mutation arose independently in all 3 pedigrees. The penetrance and expressivity of both manifestations varied considerably among individuals, suggesting that additional environmental and/or genetic factors were involved. Sevior et al. (1998) noted that all affected persons in the Turkish family described by Bititci (1975), in which 10 of 11 persons in 5 generations with progressive perceptive hearing loss also had palmoplantar keratoderma, were maternally related.
The 7445A-G mutation changes the stop codon AGA of the heavy-strand (H-strand)-encoded mRNA for subunit COI of cytochrome c oxidase to an equivalent AGG stop codon, and at the same time, changes a U-to-C transition in the light-strand (L-strand)-encoded tRNA-ser(UCN) precursor. Guan et al. (1998) investigated several lymphoblastoid cell lines from members of the New Zealand pedigree exhibiting the 7445A-G mutation in homoplasmic form. They showed that the mutation flanks the 3-prime end of the tRNA-ser(UCN) gene sequence and affects the rate but not the sites of processing of the tRNA precursor. The mutation caused an average reduction of approximately 70% in the level of tRNA-ser(UCN) and a decrease of approximately 45% in protein synthesis rate in the cell lines analyzed. Associated with the 7445A-G mutation was a marked reduction in the level of the mRNA for the ND6 subunit gene (516006), which is located approximately 7 kb upstream and is cotranscribed with the tRNA-ser(UCN) gene. Such reduction significantly affects the rate of synthesis of the ND6 subunit and plays a determinant role in the deafness-associated respiratory phenotype of the mutant cell lines. In particular, it accounts for their specific, very significant decrease in glutamate- or malate-dependent O2 consumption. Guan et al. (1998) suggested that homoplasmic mtDNA mutations affecting other subunits of NADH dehydrogenase may play a synergistic role in the establishment of the respiratory phenotype of the mutant cells, just as the penetrance of primary mutations of Leber hereditary optic neuropathy (LHON; 535000) is increased by the associated mutations. In the New Zealand pedigree, a previously undescribed rare mutation at position 10084 of the ND3 gene (516002) changed an isoleucine to a threonine, and may have been responsible for the fact that the clinical disorder had higher penetrance in the New Zealand pedigree than in the Scottish pedigree.
Martin et al. (2000) reported a French pedigree with members having an inherited combination of nonepidermolytic palmoplantar keratoderma and sensorineural deafness. The penetrance of both features was incomplete. Additional ectodermal defects were absent. The combination was shown to be associated with the 7445A-G point mutation in the mitochondrial genome (mtDNA).
Hutchin et al. (2001) described a 3-generation family from Ukraine with nonsyndromic sensorineural progressive deafness (500008) due to the homoplasmic mtDNA 7445A-G mutation. The family members showed no signs of palmoplantar keratoderma. The authors stated that all 4 reported families with this mutation have been of different ethnic backgrounds, suggesting that the mutation arose on 4 independent genetic backgrounds.
Jaksch et al. (1998) identified a 1-bp insertion at nucleotide 7472 of the MTTS1 gene in 2 patients with mitochondrial encephalopathy with cytochrome c oxidase deficiency associated with sensorineural hearing loss, ataxia, myoclonic epilepsy, and mental retardation.
In a Sicilian family with maternally inherited hearing loss as a predominant feature, Tiranti et al. (1995) found the insertion of a C at nucleotide position 7472 of the MTTS1 gene. In 6 of 9 patients, the hearing loss was accompanied by ataxia, dysarthria, and focal myoclonus. Verhoeven et al. (1999) reported a Dutch family with maternally inherited, progressive, sensorineural hearing loss (500008) in 27 patients with the same mutation. They determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leukocyte heteroplasmy. However, in the Dutch family, only a single family member with hearing loss showed accompanying neurologic symptoms including ataxia and dysarthria. Verhoeven et al. (1999) suggested that modifying secondary factors must account for the interfamilial differences in penetrance of the neurologic abnormalities. They concluded, furthermore, that this mutation should be analyzed in patients with maternally inherited hearing loss, irrespective of whether the hearing loss is nonsyndromic or accompanied by neurologic abnormalities. Three members with the 7472insC mutation developed hearing loss after the use of aminoglycosides. For this reason, Verhoeven et al. (1999) analyzed for this mutation in 52 patients who suffered from acute hearing loss after the use of aminoglycosides; 43 of these patients were unrelated. In 7 of the 43, the 1555A-G mutation (561000.0001) in the MTRNR1 gene was found, but the 7472insC mutation was not detected in any of them. This was the third mitochondrial mutation identified as the cause of hearing loss, the others being 1555A-G and 7445A-G (590080.0002), which is also in the MTTS1 gene.
Toompuu et al. (1999) performed studies of the 7472insC mutation in osteosarcoma cell cybrids. They found no evidence for a specific defect in aminoacylation, and unlike the case with the np 7445 mutation, which is also associated with deafness, the pattern of RNA processing of light strand transcripts of the ND6 region was not systematically altered. Comparison of the np 7472 and np 7445 mutant phenotypes in cultured cells suggested that sensorineural deafness can result from a functional insufficiency of mitochondrial tRNA-ser, to which some cells of the auditory system are especially vulnerable.
In 6 Western European families with the heteroplasmic 7472insC mutation in the MTTS1 gene, Hutchin et al. (2001) performed mtDNA haplotype analysis on the basis of 10 polymorphic restriction enzyme sites. The families were assigned to haplogroups K, V, and H. There were 4 families in haplogroup H, which is the most common European haplogroup (approximately 40%). Sequence analysis of the D-loop region showed that the 4 haplogroup H families were not closely related, supporting that the 7472insC mutation had occurred multiple times in the European population. The presence of the same mutation on separate mtDNA backgrounds confirmed the notion that the 7472insC mutation alone is sufficient to cause hearing loss and that when present at very high levels can also lead to neurologic dysfunction.
Hutchin et al. (2000) reported a heteroplasmic T-to-C transition at nucleotide 7510 of the MTTS1 gene in affected members of a family with sensorineural hearing loss (500008). The pattern of transmission within the family was consistent with maternal inheritance. The mutation is predicted to disrupt basepairing in the acceptor stem of the tRNA.
In a large African American family with typical maternally inherited nonsyndromic hearing loss (500008) previously reported by Friedman et al. (1999), Sue et al. (1999) identified a homoplasmic 7511T-C transition in the MTTS1 gene (590080.0005).
Chapiro et al. (2002) identified the 7411T-C transition in 2 French families with nonsyndromic deafness. The proband of the first family was diagnosed at the age of 3 years because of delay in language development with a moderate bilateral sensorineural hearing loss. The mutation was homoplasmic in the patient and in the 8 maternal relatives tested, 5 of whom had hearing impairment. The hearing loss was mild to severe with an average loss of 51 dB. The diagnosis of hearing impairment was established between 3 and 33 years of age. The hearing loss was progressive in the proband but in none of the other deaf members of the family. The proband of the second family presented with a prelingual bilateral severe sensorineural deafness. Bilateral and permanent tinnitus began when he was 20 years old. His mother and 4 of his siblings presented with hearing impairment ranging from a mild unilateral to a severe bilateral deafness and with variable age at diagnosis. The level of the mutated mtDNA was variable with homoplasmic levels in 5 and heteroplasmic levels in 9 relatives (the level of mutant mtDNA in blood, urine, hair root cells, and mouthwash samples varied from 51-85% and did not correlate with the severity of the disease). In several hetero- or homoplasmic members of the family, no known hearing problem was present. This high variability suggested the existence of genetic and/or environmental factors modifying the expression of this mutation.
Jin et al. (2007) identified a 7444G-A transition in the MTTS1 gene in 7 of 1,542 Han Chinese individuals with aminoglycoside ototoxicity (580000) or nonsyndromic sensorineural hearing loss. All 7 probands had been administered aminoglycosides between 1 to 3 years of age and began suffering hearing loss within 3 months. Two of the probands had both 7444G-A and a mutation in the MTRNR1 gene (1555A-G; 561000.0001). Family histories suggested very low penetrance for the 7444G-A mutation alone. In contrast, there were several members of the 2 families with both 7444G-A and 1555A-G who had sensorineural hearing loss without aminoglycoside exposure, indicating a higher penetrance of hearing loss in those with 2 mutations.
Jin et al. (2007) identified a 7445A-C transversion in the MTTS1 gene in a Han Chinese individual with nonsyndromic mild hearing impairment (500008). He had onset at age 10 years and no history of aminoglycoside exposure. Family history indicated a very low penetrance for the 7445A-C mutation.
Grafakou et al. (2003) identified a 7497G-A transition in the MTTS1 gene in a 13-year-old girl with exercise intolerance, muscle pain, and lactic acidemia beginning at age 7 years. Psychomotor development was normal, and she had no hearing loss. Physical examination showed normal muscle mass, power, and tone. Muscle biopsy showed ragged-red fibers (25%) and 80% COX-negative fibers, as well as enzymatic defects in respiratory complexes I, III, and IV, compatible with a mitochondrial disorder. The mutation was homoplasmic in skeletal muscle and 90% heteroplasmic in leukocytes. The patient's asymptomatic mother had about 10% heteroplasmy in leukocytes. The mutation was not found in 200 controls. Grafakou et al. (2003) emphasized that only muscle appeared to be affected in this patient and concluded that high levels of mutant mtDNA must be required in skeletal muscle to result in disease manifestations.
In affected members of a 3-generation Han Chinese family with maternally inherited mitochondrial nonsyndromic sensorineural deafness (500008), Tang et al. (2010) identified a homoplasmic 7505T-C transition in the MTTS1 gene, disrupting a conservative basepairing on the DHU stem of tRNA-ser. The mutation was not found in 449 Chinese controls. The amount of tRNA-ser in patient cells was significantly decreased (about 35% of control values). Tang et al. (2010) suggested that shortage of this protein may lead to a reduced rate of mitochondrial protein synthesis and cellular respiration defects. The severity of hearing loss in this family varied from mild to profound, and affected individuals had an average age at onset of 8 years (range 3 to 18). Two mutation carriers were unaffected, indicating incomplete penetrance. The mutational analysis identified 37 additional mtDNA variants, including a 5587T-C change in the MTTA gene (590000), which may have contributed to the phenotype, although MTTA levels in patient cells were normal.
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