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NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp) AND Spastic ataxia 4

Clinical significance:Pathogenic (Last evaluated: Dec 1, 2014)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)]

NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)

MTPAP:mitochondrial poly(A) polymerase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)
  • NC_000010.11:g.30313926T>C
  • NG_028096.1:g.40413A>G
  • NM_018109.4:c.1432A>GMANE SELECT
  • NP_060579.3:p.Asn478Asp
  • NC_000010.10:g.30602855T>C
  • Q9NVV4:p.Asn478Asp
Protein change:
N478D; ASN478ASP
UniProtKB: Q9NVV4#VAR_064907; OMIM: 613669.0001; dbSNP: rs267606900
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_018109.4:c.1432A>G - missense variant - [Sequence Ontology: SO:0001583]


Spastic ataxia 4
Ataxia, spastic, 4, autosomal recessive
MONDO: MONDO:0013354; MedGen: C3150925; Orphanet: 254343; OMIM: 613672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000020145OMIMno assertion criteria providedPathogenic
(Dec 1, 2014)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression.

Wilson WC, Hornig-Do HT, Bruni F, Chang JH, Jourdain AA, Martinou JC, Falkenberg M, Spåhr H, Larsson NG, Lewis RJ, Hewitt L, Baslé A, Cross HE, Tong L, Lebel RR, Crosby AH, Chrzanowska-Lightowlers ZM, Lightowlers RN.

Hum Mol Genet. 2014 Dec 1;23(23):6345-55. doi: 10.1093/hmg/ddu352. Epub 2014 Jul 9.

PubMed [citation]

Defective mitochondrial mRNA maturation is associated with spastic ataxia.

Crosby AH, Patel H, Chioza BA, Proukakis C, Gurtz K, Patton MA, Sharifi R, Harlalka G, Simpson MA, Dick K, Reed JA, Al-Memar A, Chrzanowska-Lightowlers ZM, Cross HE, Lightowlers RN.

Am J Hum Genet. 2010 Nov 12;87(5):655-60. doi: 10.1016/j.ajhg.2010.09.013. Epub 2010 Oct 21.

PubMed [citation]

Details of each submission

From OMIM, SCV000020145.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)


In 6 affected members of a large consanguineous family of Old Order Amish origin with spastic ataxia-4 (SPAX4; 613672), Crosby et al. (2010) identified a homozygous 1432A-G transition in exon 9 of the MTPAP gene, resulting in an asn478-to-asp (N478D) substitution in a highly conserved region in an N-P-F-E sequence. The phenotype was characterized by early childhood onset of progressive cerebellar ataxia, spastic paraparesis, dysarthria, and optic atrophy. The mutation was not found in 600 control chromosomes from individuals of European ancestry and was found in 1 of 200 control chromosomes from the same Ohio Amish community. Assays assessing mitochondrial poly(A) tails of the mitochondrial-encoded transcripts RNA14 and MTCO1 (516030) indicated that homozygous carriers of the MTPAP mutation had significantly increased percentages of oligoadenylated (less than 10 nucleotides) compared to polyadenylated (greater than 30 nucleotides) transcripts compared to unaffected parents who were heterozygous for the N478D mutation. Although the exact function of polyadenylation of mitochondrial mRNA transcripts remained unclear, the process is essential for maintaining proper mRNA expression in mitochondria, and disruption of this process leads to mitochondrial dysfunction, as shown by the neurodegeneration in this family.

Wilson et al. (2014) performed studies on fibroblasts from 2 patients and 1 unaffected obligate mutation carrier from the Amish family with SPAX4 reported by Crosby et al. (2010). Mitochondrial mRNA from patient cells showed a lack of polyadenylation and a concomitant increase in oligoadenylated species. Heterozygous cells were similar to controls, with a mild increase in oligoadenylated mRNA. Homozygous mutant cell lines showed a decrease in oxidative phosphorylation activity, as well as a severe decrease in the amounts and activities of mitochondrial complexes I and IV. The effects on the steady-state levels and translation of mRNA species in patient cells varied depending on the transcript. The findings were consistent with a selective defect in mitochondrial gene expression, and these defects could be rescued by expression of wildtype MTPAP. The mutant protein showed normal localization, but was unable to extend unadenylated MTND3 (516002) substrate in vitro, consistent with a loss of enzyme function. The addition of LRPPRC (607544)/SLIRP (610211), a mitochondrial RNA-binding complex, mildly enhanced adenylation activity of the mutant protein. Wilson et al. (2014) concluded that alterations in poly(A) length can dysregulate posttranscriptional expression and cause a pathogenic lack of respiratory chain complexes.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 23, 2022

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