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UniProtKB/Swiss-Prot Q06787: Variant p.Ile304Asn

Synaptic functional regulator FMR1
Gene: FMR1
Variant information

Variant position:  304
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Isoleucine (I) to Asparagine (N) at position 304 (I304N, p.Ile304Asn).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and hydrophobic (I) to medium size and polar (N)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Fragile X syndrome (FXS) [MIM:300624]: An X-linked dominant disease characterized by moderate to severe mental retardation, macroorchidism (enlargement of the testicles), large ears, prominent jaw, and high-pitched, jocular speech. The defect in most patients results from an amplification of a CGG repeat region in the FMR1 gene and abnormal methylation. {ECO:0000269|PubMed:10196376, ECO:0000269|PubMed:11157796, ECO:0000269|PubMed:15380484, ECO:0000269|PubMed:15805463, ECO:0000269|PubMed:17850748, ECO:0000269|PubMed:18093976, ECO:0000269|PubMed:18664458, ECO:0000269|PubMed:23235829, ECO:0000269|PubMed:24204304, ECO:0000269|PubMed:24448548, ECO:0000269|PubMed:24514761, ECO:0000269|PubMed:24813610, ECO:0000269|PubMed:25561520, ECO:0000269|PubMed:7633450, ECO:0000269|PubMed:7688265, ECO:0000269|PubMed:8156595, ECO:0000269|PubMed:8401578, ECO:0000269|PubMed:8490650, ECO:0000269|PubMed:9659908}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In FXS; alters protein folding and stability; increases nucleocytoplasmic shuttling; reduces localization in Cajal bodies; reduces the association with cytoplasmic granules; reduces association with polyribosome; reduces RNA-binding; attenuates mRNA translation repression; impairs homooligomerization; reduces interaction with TDRD3; reduces interaction with viral influenza A nucleoprotein (NP); does not inhibit interaction with SMN1, FXR1 and FXR2.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  304
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  632
The length of the canonical sequence.

Location on the sequence:   DVIQVPRNLVGKVIGKNGKL  I QEIVDKSGVVRVRIEAENEK
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 632 Synaptic functional regulator FMR1
Domain 285 – 314 KH 2
Helix 302 – 311


Literature citations

FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association.
Feng Y.; Absher D.; Eberhart D.E.; Brown V.; Malter H.E.; Warren S.T.;
Mol. Cell 1:109-118(1997)
Cited for: SUBCELLULAR LOCATION; ASSOCIATION WITH POLYRIBOSOME AND MRNP; CHARACTERIZATION OF VARIANT FXS ASN-304;

Different targets for the fragile X-related proteins revealed by their distinct nuclear localizations.
Tamanini F.; Bontekoe C.; Bakker C.E.; van Unen L.; Anar B.; Willemsen R.; Yoshida M.; Galjaard H.; Oostra B.A.; Hoogeveen A.T.;
Hum. Mol. Genet. 8:863-869(1999)
Cited for: SUBCELLULAR LOCATION; NUCLEOCYTOPLASMIC SHUTTLING; CHARACTERIZATION OF VARIANT FXS ASN-304;

Evidence that fragile X mental retardation protein is a negative regulator of translation.
Laggerbauer B.; Ostareck D.; Keidel E.M.; Ostareck-Lederer A.; Fischer U.;
Hum. Mol. Genet. 10:329-338(2001)
Cited for: FUNCTION; INTERACTION WITH FXR1 AND FXR2; SUBUNIT; RNA-BINDING; CHARACTERIZATION OF VARIANT FXS ASN-304;

Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes.
Darnell J.C.; Fraser C.E.; Mostovetsky O.; Stefani G.; Jones T.A.; Eddy S.R.; Darnell R.B.;
Genes Dev. 19:903-918(2005)
Cited for: CHARACTERIZATION OF VARIANT FXS ASN-304; RNA-BINDING; DOMAIN;

Tdrd3 is a novel stress granule-associated protein interacting with the Fragile-X syndrome protein FMRP.
Linder B.; Ploettner O.; Kroiss M.; Hartmann E.; Laggerbauer B.; Meister G.; Keidel E.; Fischer U.;
Hum. Mol. Genet. 17:3236-3246(2008)
Cited for: SUBUNIT; INTERACTION WITH TDRD3; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT FXS ASN-304;

In vitro and in cellulo evidences for association of the survival of motor neuron complex with the fragile X mental retardation protein.
Piazzon N.; Rage F.; Schlotter F.; Moine H.; Branlant C.; Massenet S.;
J. Biol. Chem. 283:5598-5610(2008)
Cited for: INTERACTION WITH SMN; ASSOCIATION WITH THE SMN CORE COMPLEX; SUBCELLULAR LOCATION; CHARACTERIZATION OF VARIANT FXS ASN-304;

FMRP targets distinct mRNA sequence elements to regulate protein expression.
Ascano M. Jr.; Mukherjee N.; Bandaru P.; Miller J.B.; Nusbaum J.D.; Corcoran D.L.; Langlois C.; Munschauer M.; Dewell S.; Hafner M.; Williams Z.; Ohler U.; Tuschl T.;
Nature 492:382-386(2012)
Cited for: FUNCTION; RNA-BINDING; CHARACTERIZATION OF VARIANT FXS ASN-304;

Nuclear fragile X mental retardation protein is localized to Cajal bodies.
Dury A.Y.; El Fatimy R.; Tremblay S.; Rose T.M.; Cote J.; De Koninck P.; Khandjian E.W.;
PLoS Genet. 9:E1003890-E1003890(2013)
Cited for: FUNCTION (ISOFORMS 6 AND 10); SUBCELLULAR LOCATION (ISOFORMS 6; 9; 10 AND 11); PROTEOLYTIC PROCESSING (ISOFORM 10); RNA-BINDING (ISOFORMS 6 AND 10); DOMAIN (ISOFORM 10); TISSUE SPECIFICITY; CHARACTERIZATION OF VARIANT FXS ASN-304 (ISOFORM 10);

Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus.
Zhou Z.; Cao M.; Guo Y.; Zhao L.; Wang J.; Jia X.; Li J.; Wang C.; Gabriel G.; Xue Q.; Yi Y.; Cui S.; Jin Q.; Wang J.; Deng T.;
Nat. Commun. 5:3259-3259(2014)
Cited for: FUNCTION (MICROBIAL INFECTION); INTERACTION WITH INFLUENZA A NP (MICROBIAL INFECTION); CHARACTERIZATION OF VARIANT FXS ASN-304 (MICROBIAL INFECTION); INDUCTION (MICROBIAL INFECTION);

Fragile X mental retardation syndrome: structure of the KH1-KH2 domains of fragile X mental retardation protein.
Valverde R.; Pozdnyakova I.; Kajander T.; Venkatraman J.; Regan L.;
Structure 15:1090-1098(2007)
Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 397-425; CHARACTERIZATION OF VARIANT FXS ASN-304;

A point mutation in the FMR-1 gene associated with fragile X mental retardation.
de Boulle K.; Verkerk A.J.M.H.; Reyniers E.; Vits L.; Hendrickx J.; van Roy B.; van den Bos F.; de Graaff E.; Oostra B.A.; Willems P.J.;
Nat. Genet. 3:31-35(1993)
Cited for: VARIANT FXS ASN-304;

Essential role for KH domains in RNA binding: impaired RNA binding by a mutation in the KH domain of FMR1 that causes fragile X syndrome.
Siomi H.; Choi M.; Siomi M.C.; Nussbaum R.L.; Dreyfuss G.;
Cell 77:33-39(1994)
Cited for: CHARACTERIZATION OF VARIANT FXS ASN-304; RNA-BINDING;

Characterization of FMR1 proteins isolated from different tissues.
Verheij C.; de Graaff E.; Bakker C.E.; Willemsen R.; Willems P.J.; Meijer N.; Galjaard H.; Reuser A.J.J.; Oostra B.A.; Hoogeveen A.T.;
Hum. Mol. Genet. 4:895-901(1995)
Cited for: CHARACTERIZATION OF VARIANT FXS ASN-304;

Transport kinetics of FMRP containing the I304N mutation of severe fragile X syndrome in neurites of living rat PC12 cells.
Schrier M.; Severijnen L.A.; Reis S.; Rife M.; van't Padje S.; van Cappellen G.; Oostra B.A.; Willemsen R.;
Exp. Neurol. 189:343-353(2004)
Cited for: CHARACTERIZATION OF VARIANT FXS ASN-304; INTERACTION WITH FXR1 AND RPLP0; SUBCELLULAR LOCATION;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.