Human Disease Model Report: spermatogenic failure, X-linked, 9

General Information

Name

spermatogenic failure, X-linked, 9

FlyBase ID

FBhh0001480

Disease Ontology Term

X-linked spermatogenic failure 9

Parent Disease

azoospermia, non-obstructive

OMIM

SPERMATOGENIC FAILURE, X-LINKED, 9; SPGFX9

Overview

The X-linked human gene RBBP7 has been shown to play a key role in spermatogenesis; its deficiency has been postulated to lead to inherited predisposition to non-obstructive azoospermia and to the potential development of testicular tumors. There is a single fly ortholog, Caf1-55, for which multiple genetic reagents have been generated, including loss-of-function alleles, RNAi-targeting constructs, alleles caused by insertional mutagenesis, overexpression constructs, and a CRISPR/Cas9-based LOF construct.

Initially identified in a large-scale analysis of X chromosome-linked protein-coding genes in 2,354 azoospermic/cryptozoospermic men from four independent and geographically separate cohorts, RBBP7 was found to be mutated in ten men across all cohorts. A subsequent study identified a variant of RBBP7 in two brothers with non-obstructive azoospermia; one brother also had a small testicular tumor.

UAS constructs of the human Hsap\RBBP7 gene have been introduced into flies, including a construct carrying a variant implicated in this disease. Heterologous rescue (functional complementation) is observed: wild-type human RBBP7 rescues male infertility in Caf1-55-deficient Drosophila; however, RBBP7 carrying the disease-implicated variant fails to rescue. (See the 'Disease-Implicated Variants' table, below.)

In Drosophila, animals homozygous for a null mutation of Caf1-55 typically die during the larval stage. In Drosophila males, knockdown of Caf1-55 in germ cells, using tissue-specific GAL4/UAS-RNAi, results in reduced underdeveloped testes and loss of male germline stem cells. Knockdown in the somatic cyst cells of the testis results in hyperproliferative testicular cells.

[updated Jan. 2024 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: azoospermia, non-obstructive

Symptoms and phenotype

Non-obstructive azoospermia (NOA) is defined as absence of any measurable level of sperm in semen, resulting from a defect in the production of spermatozoa in the testes. [from MedGen, Non-obstructive azoospermia; MedGen UID: 866757]

(FlyBase Curators, 2013-)

Non-obstructive azoospermia (NOA), or failure of spermatogenesis within the testis, is diagnosed in approximately 10% of infertile men. NOA may be due to a lack of appropriate stimulation by gonadotropins, in which case hormonal therapy is usually effective. A larger category of non-obstructive azoospermia consists of men with an intrinsic testicular impairment. In these cases, the primary approach is to improve the quantity and quality of sperm retrieved from the testis for use for in vitro fertilization (Kumar, 2013; PMCID:PMC3583162).

(FlyBase Curators, 2013-)

Specific Disease Summary: spermatogenic failure, X-linked, 9

OMIM report

[SPERMATOGENIC FAILURE, X-LINKED, 9; SPGFX9](https://omim.org/entry/301137)

Human gene(s) implicated

[RETINOBLASTOMA-BINDING PROTEIN 7; RBBP7](https://omim.org/entry/300825)

Symptoms and phenotype

X-linked spermatogenic failure-9 (SPGFX9) is characterized by male infertility due to nonobstructive azoospermia resulting from maturation arrest. [from MIM:301137; 2025.03.08]

(OMIM, 2013-)

Observation of non-obstructive azoospermia (NOA).

(Riera-Escamilla et al., 2022)

Genetics

X-linked spermatogenic failure-9 (SPGFX9) is caused by hemizygous mutation in the RBBP7 gene. [from MIM:301137; 2025.03.08]

(OMIM, 2013-)

[from MIM:***; 2024..]

(OMIM, 2013-)

Locus identified in large-scale analysis of X-linked mutations in men with non-obstructive azoospermia.

(Riera-Escamilla et al., 2022)

Cellular phenotype and pathology

Molecular information

RBBP7 (RB binding protein 7, chromatin remodeling factor) is a core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. [from Uniprot:Q16576; 2022.11.02]

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): RBBP7
Gene Cards: RBBP7
MedlinePlus (gene): RBBP7
MARRVEL (human gene): RBBP7
NCBI (Entrez) gene: RBBP7; RB binding protein 7, chromatin remodeling factor

Disease synonyms

azoospermia (postulated), RBBP7-related

azoospermia and testicular cancer (postulated), RBBP7-related

male infertility

NOA

non-obstructive azoospermia

Search term: Leydig cell tumor

SPGFX9

Related Diseases

Related human health report(s)

azoospermia, non-obstructive

Related Specific Diseases

OMIM phenotypic series

Spermatogenic failure

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[SPGFX9](https://omim.org/entry/301137)

[RBBP7](https://omim.org/entry/300825)

spermatogenic failure, X-linked, 9

Ortholog Information

Human gene(s) in FlyBase

Hsap\RBBP7

Human gene (HGNC)

Symbol / Name

RBBP7; RB binding protein 7, chromatin remodeling factor

D. melanogaster ortholog (based on DIOPT)

Dmel\Caf1-55

(DIOPT, 2013-)

Comments on ortholog(s)

two to one: human gene to Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\Caf1-55

Gene Snapshot

Chromatin assembly factor 1, p55 subunit (Caf1-55) encodes a subunit of the MuvB core complex. The MuvB core binds to the oncoprotein encoded by Myb and the Rbf-E2f2-Dp tumor suppressor complex, thereby controlling the expression of many genes, including critical regulators of the cell cycle. [Date last reviewed: 2019-03-21]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human RBBP4 and RBBP7; (1 Drosophila to 2 human).

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 (62 groups)

Caf1-55

protein-protein

Interacting group

Assay

References

Caf1-55 - arm

pull down, western blot

(Song et al., 2009)

Caf1-55 - arx

anti tag coimmunoprecipitation, western blot

(Mugat et al., 2020)

Caf1-55 - ash1

tandem affinity purification, Identification by mass spectrometry, anti bait coimmunoprecipitation, western blot, affinity technology, anti tag coimmunoprecipitation, molecular weight estimation by staining

(Schmähling et al., 2018, Huang et al., 2017)

Caf1-55 - bon

anti tag coimmunoprecipitation, anti tag western blot

(Godneeva et al., 2023)

Caf1-55 - Caf1-105

anti bait coimmunoprecipitation, peptide massfingerprinting, ion exchange chromatography, molecular weight estimation by staining

(Doyen et al., 2013, Tyler et al., 1996)

Caf1-55 - Caf1-180

anti tag coimmunoprecipitation, western blot, ion exchange chromatography, anti bait coimmunoprecipitation, molecular weight estimation by staining

(Demirdizen et al., 2019, Tyler et al., 1996)

Caf1-55 - CDK2AP1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Zhang et al., 2016)

Caf1-55 - cid

anti tag coimmunoprecipitation, anti tag western blot, pull down, molecular weight estimation by coomasie staining, Identification by mass spectrometry, peptide massfingerprinting, autoradiography, cross-linking study, western blot, tandem affinity purification

(Demirdizen et al., 2019, Boltengagen et al., 2016, Furuyama and Henikoff, 2006, Furuyama et al., 2006)

Caf1-55 - Cp190

anti tag coimmunoprecipitation, anti bait coimmunoprecipitation, western blot

(Bohla et al., 2014)

Caf1-55 - CTCF

anti tag coimmunoprecipitation, anti bait coimmunoprecipitation, western blot

(Bohla et al., 2014)

Caf1-55 - Dref

anti bait coimmunoprecipitation, western blot

(Hochheimer et al., 2002)

Caf1-55 - E(bx)

ion exchange chromatography, cosedimentation, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot

(Lam et al., 2019, Kwon et al., 2009, Tsukiyama and Wu, 1995, Tsukiyama et al., 1995)

Caf1-55 - E(z)

chromatography technology, molecular weight estimation by staining, anti tag coimmunoprecipitation, ion exchange chromatography, western blot, tandem affinity purification, Identification by mass spectrometry, pull down, autoradiography

(Kang et al., 2015, Yuan et al., 2012, Margueron et al., 2009, Ohno et al., 2008, Ketel et al., 2005, Nekrasov et al., 2005, Czermin et al., 2002, Tie et al., 2001)

Caf1-55 - esc

anti tag coimmunoprecipitation, molecular weight estimation by staining, ion exchange chromatography, western blot, chromatography technology, pull down, peptide massfingerprinting

(Seif and Francis, 2024, Wang et al., 2018, Kang et al., 2017, Kang et al., 2015, Rai et al., 2013, Yuan et al., 2012, Ketel et al., 2005, Czermin et al., 2002, Muller et al., 2002, Tie et al., 2001)

Caf1-55 - escl

anti bait coimmunoprecipitation, western blot

(Kurzhals et al., 2008)

Caf1-55 - foxo

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Caf1-55 - gig

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Caf1-55 - Hat1

molecular sieving, anti tag coimmunoprecipitation, western blot, peptide massfingerprinting

(Boltengagen et al., 2016)

Caf1-55 - HDAC1

pull down, western blot, molecular sieving, molecular weight estimation by staining, autoradiography, anti tag coimmunoprecipitation, Identification by mass spectrometry, ion exchange chromatography

(Mugat et al., 2020, Zhang et al., 2016, Tie et al., 2003, Czermin et al., 2002, Tie et al., 2001)

Caf1-55 - His2A

pull down, autoradiography

(Tie et al., 2007)

Caf1-55 - His3

anti bait coimmunoprecipitation, western blot, pull down, anti tag western blot, molecular sieving, molecular weight estimation by staining, x-ray crystallography, surface plasmon resonance, fluorescence polarization spectroscopy, predetermined participant, isothermal titration calorimetry, cosedimentation, molecular weight estimation by silver staining

(Doyen et al., 2013, Nowak et al., 2011, Schmitges et al., 2011, Song et al., 2008, Wysocka et al., 2006)

Caf1-55 - His4

pull down, molecular weight estimation by staining, autoradiography, molecular sieving, x-ray crystallography, predetermined participant, surface plasmon resonance, isothermal titration calorimetry, cosedimentation

(Nowak et al., 2011, Schmitges et al., 2011, Song et al., 2008, Tie et al., 2007, Furuyama et al., 2006)

Caf1-55 - Iswi

anti bait coimmunoprecipitation, western blot, ion exchange chromatography, cosedimentation, molecular weight estimation by staining, peptide massfingerprinting

(Doyen et al., 2015, Gdula et al., 1998, Martinez-Balbas et al., 1998, Tsukiyama and Wu, 1995, Tsukiyama et al., 1995)

Caf1-55 - Jarid2

anti tag coimmunoprecipitation, multidimensional protein identification technology

(Herz et al., 2012)

Caf1-55 - lin-52

anti tag coimmunoprecipitation, western blot

(Lewis et al., 2012)

Caf1-55 - Marf1

anti tag coimmunoprecipitation, western blot

(Zhu et al., 2018)

Caf1-55 - MBD-like

molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, Identification by mass spectrometry

(Zhang et al., 2016)

Caf1-55 - MBD-R2

anti bait coimmunoprecipitation, western blot

(Lam et al., 2019)

Caf1-55 - MEP-1

anti bait coimmunoprecipitation, Identification by mass spectrometry, molecular sieving, molecular weight estimation by staining, western blot

(Mugat et al., 2020, Reddy et al., 2010)

Caf1-55 - Mi-2

anti bait coimmunoprecipitation, Identification by mass spectrometry, molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, western blot

(Mugat et al., 2020, Zhang et al., 2016, Fasulo et al., 2012, Reddy et al., 2010)

Caf1-55 - mip40

anti bait coimmunoprecipitation, western blot, affinity chromatography technology, Identification by mass spectrometry

(Beall et al., 2007, Beall et al., 2002)

Caf1-55 - mip120

anti bait coimmunoprecipitation, western blot

(Lewis et al., 2004, Beall et al., 2002)

Caf1-55 - mip130

anti bait coimmunoprecipitation, western blot

(Lewis et al., 2004, Beall et al., 2002)

Caf1-55 - MRG15

affinity technology, molecular weight estimation by staining, anti bait coimmunoprecipitation, western blot

(Schmähling et al., 2018, Huang et al., 2017)

Caf1-55 - mrt

anti tag coimmunoprecipitation, anti tag western blot

(Yao et al., 2018)

Caf1-55 - MTA1-like

molecular sieving, molecular weight estimation by staining, anti tag coimmunoprecipitation, western blot, Identification by mass spectrometry

(Mugat et al., 2020, Demirdizen et al., 2019, Zhang et al., 2016)

Caf1-55 - Myb

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation

(Andrejka et al., 2011, Wen et al., 2008, Lewis et al., 2004, Beall et al., 2002)

Caf1-55 - N

anti tag coimmunoprecipitation, anti tag western blot

(Yu et al., 2013)

Caf1-55 - Nap1

anti bait coimmunoprecipitation, western blot

(Stephens et al., 2006)

Caf1-55 - nsl1

anti bait coimmunoprecipitation, western blot

(Lam et al., 2019)

Caf1-55 - Nurf-38

ion exchange chromatography, cosedimentation, molecular weight estimation by staining, anti bait coimmunoprecipitation, western blot

(Gdula et al., 1998, Tsukiyama and Wu, 1995, Tsukiyama et al., 1995)

Caf1-55 - Pcl

anti bait coimmunoprecipitation, western blot

(Tie et al., 2003)

Caf1-55 - piwi

anti bait coimmunoprecipitation, western blot

(Mugat et al., 2020)

Caf1-55 - Pten

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Caf1-55 - pzg

anti bait coimmunoprecipitation, western blot

(Kugler and Nagel, 2010)

Caf1-55 - Rbf

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, coimmunoprecipitation

(Lee et al., 2012, Korenjak et al., 2004, Taylor-Harding et al., 2004)

Caf1-55 - Rbf2

anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot

(Korenjak et al., 2004, Taylor-Harding et al., 2004)

Caf1-55 - Rcd5

anti bait coimmunoprecipitation, western blot

(Lam et al., 2019)

Caf1-55 - rictor

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Caf1-55 - S6kII

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Caf1-55 - sima

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Caf1-55 - simj

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Zhang et al., 2016)

Caf1-55 - Sin3A

anti tag coimmunoprecipitation, western blot, peptide massfingerprinting

(Spain et al., 2010)

Caf1-55 - Sirt1

anti bait coimmunoprecipitation, western blot

(Furuyama et al., 2004)

Caf1-55 - smg

anti bait coimmunoprecipitation, western blot

(Zaessinger et al., 2006)

Caf1-55 - Su(var)2-HP2

anti bait coimmunoprecipitation, western blot

(Stephens et al., 2006)

Caf1-55 - Su(z)12

anti tag coimmunoprecipitation, molecular weight estimation by staining, isothermal titration calorimetry, predetermined participant, ion exchange chromatography, western blot, pull down, x-ray crystallography, chromatography technology

(Yuan et al., 2012, Nowak et al., 2011, Schmitges et al., 2011, Ketel et al., 2005, Nekrasov et al., 2005, Czermin et al., 2002)

Caf1-55 - Trf2

anti bait coimmunoprecipitation, western blot

(Hochheimer et al., 2002)

Caf1-55 - Tsc1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

Caf1-55 - ush

anti tag coimmunoprecipitation, western blot

(Lenz et al., 2021)

RNA-protein

Interacting group