Human Disease Model Report: short stature, hearing loss, retinitis pigmentosa, and distinctive facies

General Information

Name

short stature, hearing loss, retinitis pigmentosa, and distinctive facies

FlyBase ID

FBhh0001213

Disease Ontology Term

short stature, hearing loss, retinitis pigmentosa, and distinctive facies

Parent Disease

OMIM

SHORT STATURE, HEARING LOSS, RETINITIS PIGMENTOSA, AND DISTINCTIVE FACIES; SHRF

Overview

This report describes a syndrome defined as short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF), which shows autosomal recessive inheritance. The human gene implicated in this disease is EXOSC2, also known as RRP4. There is a single, high-ranking ortholog of EXOSC2 in Drosophila, Rrp4. Some alleles have been generated of Rrp4, including alleles carrying RNAi targeting constructs, and alleles generated by insertional transgenesis.

The human gene Hsap\EXOSC2 has been introduced into flies, as wild-type and as a disease-associated variant (EXOSC2 p.Gly30Val).

Ubiquitous knockdown of Rrp4 causes larval lethality, but eye-specific knockdown results in small rough eyes. This phenotype can be partially rescued by wild-type but not mutant (disease associated variant) Hsap\EXOSC2, demonstrating heterologous rescue (functional complementation). Examination of the eyes of Rrp4 hypomorphs shows a normal retina, but disorganized lamina lacking photoreceptor structure. The muscles of Rrp4 hypomorphs have a disrupted Z line, increased mitochondrial mass, large glycogen deposits, and sarcomeric shortening. Activating Rrp4 knockout in late third instar larvae by heat-shock downregulates multiple autophagy genes. Promoting autophagy by rapamycin and by overexpression of autophagy genes can rescue eye phenotypes caused by Rrp4 knockdown.

[updated Apr. 2020 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: short stature, hearing loss, retinitis pigmentosa, and distinctive facies

OMIM report

[SHORT STATURE, HEARING LOSS, RETINITIS PIGMENTOSA, AND DISTINCTIVE FACIES; SHRF](https://omim.org/entry/617763)

Human gene(s) implicated

[EXOSOME COMPONENT 2; EXOSC2](https://omim.org/entry/602238)

Symptoms and phenotype

SHRF is an autosomal recessive disorder characterized by short stature, brachydactyly, dysmorphic facial features, hearing loss, and visual impairment. Onset of the hearing and visual abnormalities, including retinitis pigmentosa, varies from birth to the second decade. Patients have mild intellectual disability and mild cerebellar atrophy with myelination defects on brain imaging (summary by Di Donato et al. 2016, pubmed:26843489). [from MIM:617763, 2020.04.29]

(OMIM, 2013-)

SHRF patients exhibit childhood myopia, early onset retinitis pigmentosa, progressive sensorineural hearing loss, short stature, brachydactyly, a recognizable facial gestalt, premature skin aging, mild cerebellar atrophy, and mild intellectual disability. (From Yang et al. 2020, FBrf0245116.)

(FlyBase Curators, 2013-)

Genetics

In 3 patients from 2 unrelated German families with short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF; 617763), Di Donato et al. 2016 (pubmed:26843489) identified homozygous or compound heterozygous mutations in the EXOSC2 gene (G30V and G198D). The mutations, which were found by whole-exome sequencing, segregated with the disorder in both families. The G30V variant was found in all 3 patients and at a low frequency in German controls, suggesting a common founder allele in this population. [from MIM:602238, 2020.04.29]

(OMIM, 2013-)

To date, sequencing of SHRF patients from two unrelated families has identified missense mutations in the EXOSC2 gene. Two of the patients have Gly30Val (G30V) homozygous mutations in the N-terminal domain, and one patient carries the above Gly30Val mutation in trans to Gly198Asp (G30V/G198D), with the G198D mutation located in the K Homology (KH) RNA-binding domain, named after the heterogeneous nuclear ribonucleoprotein K. (From Yang et al. 2020 and references therein, FBrf0245116.)

(FlyBase Curators, 2013-)

Cellular phenotype and pathology

Molecular information

The EXOCS2 gene encodes ribosomal RNA-processing protein-4 (RRP4), a core component of the RNA exosome. The RNA exosome is a multiprotein complex that plays key roles in RNA processing and degradation (summary by Di Donato et al. 2016, pubmed:26843489). [from MIM:602238, 2020.04.29]

(OMIM, 2013-)

External links

Gene2Function (human gene): 23404
Gene2Function (human gene): EXOSC2
Gene Cards: EXOSC2
MedlinePlus (gene): EXOSC2
MARRVEL (human gene): EXOSC2
NCBI MedGen: Retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome (SHRF)
NCBI (Entrez) gene: EXOSC2; exosome component 2

Disease synonyms

SHRF

Related Diseases

Related human health report(s)

Ortholog Information

Human gene(s) in FlyBase

Hsap\EXOSC2

Human gene (HGNC)

Symbol / Name

EXOSC2; exosome component 2

D. melanogaster ortholog (based on DIOPT)

Dmel\Rrp4

(DIOPT, 2013-)

Comments on ortholog(s)

One to one: 1 human gene to 1 Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Rrp4

Gene Snapshot

Rrp4 (Rrp4) encodes a protein involved in gene expression regulation. [Date last reviewed: 2019-07-11]

Molecular function (GO)

RNA binding

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Single, very high-scoring ortholog of Hsap\EXOSC2,

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (11 groups)

Rrp4

protein-protein

Interacting group

Assay

References

Rrp4 - Cp190

anti bait coimmunoprecipitation, western blot

(Lim et al., 2013)

Rrp4 - Csl4

experimental knowledge based

(Guruharsha et al., 2011)

Rrp4 - Dis3

anti tag coimmunoprecipitation, western blot, experimental knowledge based

(Guruharsha et al., 2011, Mamolen et al., 2010, Graham et al., 2009)

Rrp4 - Mtr3

experimental knowledge based

(Guruharsha et al., 2011)

Rrp4 - Polr2A

anti tag coimmunoprecipitation, western blot

(Hessle et al., 2009)

Rrp4 - Rrp6

experimental knowledge based

(Guruharsha et al., 2011)

Rrp4 - Rrp40

experimental knowledge based

(Guruharsha et al., 2011)

Rrp4 - Rrp42

experimental knowledge based

(Guruharsha et al., 2011)

Rrp4 - Rrp46

experimental knowledge based

(Guruharsha et al., 2011)

Rrp4 - rump

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, Identification by mass spectrometry

(Hessle et al., 2009)

Rrp4 - Ski6

experimental knowledge based

(Guruharsha et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (8 alleles)

Hsap\EXOSC2

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

Hsap\EXOSC2^UAS.cYa

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC

(Yang et al., 2020)

CEA

(Yang et al., 2020)

Hsap\EXOSC2^G30V.UAS

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC

(Yang et al., 2020)

CEA

(Yang et al., 2020)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Hsap\EXOSC2^UAS.cYa

ameliorates short stature, hearing loss, retinitis pigmentosa, and distinctive facies

modeled by Rrp4^KK108526

(Yang et al., 2020)

Rrp4

Models Based on Experimental Evidence ( 6 )

Allele

Disease

Evidence

References

Rrp4^c00021

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC with Rrp4^e00463

(Yang et al., 2020)

CEC

(Yang et al., 2020)

CEA with Rrp4^e00463

(Yang et al., 2020)

CEA

(Yang et al., 2020)

Rrp4^e00463

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC with Rrp4^c00021

(Yang et al., 2020)

CEA with Rrp4^c00021

(Yang et al., 2020)

Rrp4^KK108526

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC

(Yang et al., 2020)

CEA

(Yang et al., 2020)

Rrp4^M13

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC

(Yang et al., 2020)

CEA

(Yang et al., 2020)

Rrp4^M39

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC

(Yang et al., 2020)

CEA

(Yang et al., 2020)

Rrp4^M48

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

CEC

(Yang et al., 2020)

CEA

(Yang et al., 2020)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Rrp4^KK108526

model of short stature, hearing loss, retinitis pigmentosa, and distinctive facies

is ameliorated by Atg1^UAS.cSa

(Yang et al., 2020)

is ameliorated by Atg17^EY03045

(Yang et al., 2020)

is ameliorated by Hsap\EXOSC2^UAS.cYa

(Yang et al., 2020)

is ameliorated by Mitf^UAS.Tag:HA

(Yang et al., 2020)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\EXOSC2^UAS.cYa

PBac{UAS-hEXOSC2.Y}

Hsap\EXOSC2^G30V.UAS

PBac{UAS-hEXOSC2.G30V}

Hsap\EXOSC2^UAS.Tag:HA

PBac{UAS-hEXOSC2.HA}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Rrp4^GD11114

P{GD11114}

w¹¹¹⁸; P{GD11114}v26309/TM3

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

CRISPR/Cas9

CRISPR/Cas9

CRISPR/Cas9

piggyBac activity

piggyBac activity

References (5)

Report Sections

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