title: A mutation in the nuclear pore complex gene Tmem48 causes gametogenesis defects in skeletal fusions with sterility (sks) mice.
abstract: Skeletal fusions with sterility (sks) is an autosomal recessive mutation of mouse that results in male and female sterility because of defects in gametogenesis. The mutants also have skeletal malformations with fused vertebrae and ribs. We examined testicular phenotypes of sks/sks mice to investigate the defects in spermatogenesis. Histological and immunocytochemical analyses and expression analyses of the marker genes demonstrated that spermatogenesis is arrested at mid to late pachytene stage of meiotic prophase with defective synapsis of the homologous chromosomes. Next, we determined the precise chromosomal localization of the sks locus on a 0.3-Mb region of mouse chromosome 4 by linkage analysis. By sequencing the positional candidate genes in this region and whole exome sequencing, we found a GG to TT nucleotide substitution in exon 6 of the Tmem48 gene that encodes a putative transmembrane protein with six transmembrane domains. The nucleotide substitution causes aberrant splicing, which deletes exon 6 of the Tmem48 transcript. Specific expression of TMEM48 was observed in germ cells of males and females. Furthermore, the phenotypes of the sks mutant were completely rescued by the transgenesis of a genomic fragment containing the wild-type Tmem48 gene. These findings indicate that the Tmem48 mutation is responsible for the gametogenesis defects and skeletal malformations in the sks mice. The TMEM48 protein is a nuclear membrane protein comprising the nuclear pore complex; its exact function in the nuclear pore complex is still unknown. Our finding suggested that the nuclear pore complex plays an important role in mammalian gametogenesis and skeletal development.
authors.affiliation: From the Graduate School of Environmental and Life Science and.
authors.forename: Kouyou
authors.initials: K
authors.lastname: Akiyama
authors.forename: Junko
authors.initials: J
authors.lastname: Noguchi
authors.forename: Michiko
authors.initials: M
authors.lastname: Hirose
authors.forename: Shimpei
authors.initials: S
authors.lastname: Kajita
authors.forename: Kentaro
authors.initials: K
authors.lastname: Katayama
authors.forename: Maryam
authors.initials: M
authors.lastname: Khalaj
authors.forename: Takehito
authors.initials: T
authors.lastname: Tsuji
authors.forename: Heather
authors.initials: H
authors.lastname: Fairfield
authors.forename: Candice
authors.initials: C
authors.lastname: Byers
authors.forename: Laura
authors.initials: L
authors.lastname: Reinholdt
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ogura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kunieda
mesh_terms: D000818:Animals; D001847:Bone Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023902:Chromosome Pairing / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056426:Genetic Loci; D007247:Infertility, Female / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D013091:Spermatogenesis / Q000235:genetics*
chemical_list: D028861:Nuclear Pore Complex Proteins
keywords: Meiosis; Mutant; Nuclear Membrane; Spermatogenesis; Synapses
references.citation: Development. 2010 May;137(10):1699-707
references.pmid: 20430745
references.citation: Biol Reprod. 2012 Feb 29;86(2):45
references.pmid: 22011390
references.citation: Mol Biol Cell. 2005 May;16(5):2382-94
references.pmid: 15703211
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W187-90
references.pmid: 15215377
references.citation: J Reprod Dev. 2008 Jun;54(3):203-7
references.pmid: 18408354
references.citation: Nat Rev Mol Cell Biol. 2010 Jul;11(7):490-501
references.pmid: 20571586
references.citation: Cell Signal. 2011 Oct;23(10):1555-62
references.pmid: 21683138
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3568-71
references.pmid: 12824367
references.citation: Dev Biol. 2001 Jan 15;229(2):468-79
references.pmid: 11203703
references.citation: Nat Rev Genet. 2002 Apr;3(4):285-98
references.pmid: 11967553
references.citation: Mol Biol Cell. 1998 Oct;9(10):2839-55
references.pmid: 9763447
references.citation: Nat Cell Biol. 2002 Oct;4 Suppl:s41-9
references.pmid: 12479614
references.citation: Mol Cell. 2006 Apr 7;22(1):93-103
references.pmid: 16600873
references.citation: Development. 1997 Nov;124(22):4595-603
references.pmid: 9409676
references.citation: Annu Rev Genet. 1998;32:619-97
references.pmid: 9928494
references.citation: Cell. 1986 Jan 17;44(1):65-76
references.pmid: 3510081
references.citation: J Cell Sci. 1978 Apr;30:331-52
references.pmid: 348712
references.citation: Gamete Res. 1988 Dec;21(4):409-23
references.pmid: 3220432
references.citation: Genome Biol. 2011 Sep 14;12(9):R86
references.pmid: 21917142
references.citation: Nat Rev Mol Cell Biol. 2001 Aug;2(8):621-7
references.pmid: 11483995
references.citation: J Cell Sci. 2004 Aug 15;117(Pt 18):4025-32
references.pmid: 15316078
references.citation: J Cell Biol. 2006 May 22;173(4):509-19
references.pmid: 16702233
references.citation: J Cell Biol. 1998 Sep 7;142(5):1195-207
references.pmid: 9732281
references.citation: J Cell Biol. 1978 Aug;78(2):401-14
references.pmid: 357437
references.citation: J Cell Biol. 1977 Jul;74(1):68-85
references.pmid: 874003
references.citation: Hum Mutat. 1999 Dec;14(6):543-4
references.pmid: 10571956
references.citation: Nat Rev Genet. 2010 Feb;11(2):124-36
references.pmid: 20051984
references.citation: J Cell Biol. 1993 Aug;122(4):743-51
references.pmid: 8349727
references.citation: J Reprod Dev. 2008 Apr;54(2):122-8
references.pmid: 18277055
references.citation: Trends Biochem Sci. 2000 Mar;25(3):106-10
references.pmid: 10694877