FXS_FMR1

Gene: FMR1
Disease: FXS
Inheritance: XD
Classification: Definitive
Total Score: 14
Publications Reviewed: 13
Publication Span: 39.09 years
Last Updated: 08/18/2025
Curator(s): Macayla Weiner, Harriet Dashnow

Description

Fragile X syndrome (FXS) is caused by full-mutation expansion of the CGG repeat (typically >200 repeats) in the 5′ untranslated region of FMR1. The full mutation leads to repeat-region hypermethylation, transcriptional silencing of FMR1, and reduced or absent FMRP, an RNA-binding protein involved in synaptic protein translation, brain development, and synaptic plasticity. The FMR1 full-mutation FXS locus-disease relationship is established and replicated over time.

All CriTRia Curations

Genetic evidence

Total: 8.5


Singular Evidence	Probands	PMID:2031184	6	This study investigated 28 independent families to analyze the instability of a 550-base pair DNA segment in fragile X syndrome. They demonstrated that unaffected mothers of affected children had premutations (55–200 repeats) that expand to the full mutation (>200 repeats) when passed to their offspring.
Collective Evidence	Allele	PMID:35148024	1	In a large cohort of 487 males with Fragile X syndrome, methylation mosaicism was associated with milder cognitive and behavioral impairment, including higher IQ and adaptive behavior and less social impairment. In contrast, size mosaicism was not associated with improved outcomes compared with full mutation cases.
Collective Evidence	Segregation	PMID:6712153 PMID:3838733 PMID:1673303 PMID:2903666 PMID:1710175	1.5	Two large segregation studies analyzed a cumulative 206 Fragile X pedigrees (pmid:6712153; pmid:3838733). They found an anomalous 80% penetrance in males, formalizing the existence of asymptomatic transmitting males (likelihood ratio test statistic chi^2 = 29.54, P < 0.0001). This 'Sherman Paradox' predicted instability/anticipation. Later, RFLP studies identified the region containing FRAXA (now FMR1) as the likely location of the causative gene (pmid:1673303; pmid:2903666). The locus was finally cloned and identified to be a repeat expansion (pmid:1710175)

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Experimental evidence

Total: 5.5


Function	Biochemical function	PMID:22483044	0.5	Gene-level evidence: FMRP is an RNA‐binding protein involved in the control of local translation, which has pleiotropic effects, in particular on synaptic function.
Function	Protein interaction	PMID:22483044	0.5	Supports FMRP RNA-binding/synaptic translation function at gene level.
Function	Regulatory impact	PMID:30642066	0.5	Full-mutation FXS (>200 CGG repeats) causes repeat-region hypermethylation and FMR1 transcriptional silencing, reducing FMRP; X-inactivation in females modulates FMRP expression and phenotypic variability. The ratio of cells that have the affected X active to silenced is thought to significantly affect the level of FMRP expression in the developing central nervous system.
Models	Non-human model organism	PMID:36692473 PMID:8033209 PMID:16257225 PMID:31364704	4	Several mouse models are reviewed in PMID: 36692473. Multiple Fmr1 knockout and conditional knockout mouse models recapitulate core Fragile X syndrome features, including learning deficits, hyperactivity, abnormal neural oscillations, and disrupted excitatory–inhibitory balance, supporting loss of FMRP as the primary disease mechanism in FXS. In contrast, CGG‑repeat knock‑in mice do not silence Fmr1 and instead show elevated Fmr1 mRNA with near‑normal FMRP, modeling premutation disorders (FXTAS/FXPOI) rather than FXS. Representative KO models include an exon 5 deletion causing macroorchidism, learning deficits, and hyperactivity (PMID: 8033209), and a forebrain excitatory neuron–specific conditional KO (exon 1 deletion) resulting in abnormal brain rhythms, reduced inhibitory neuron support, and hyperactivity (PMIDs: 16257225, 31364704).

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Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.