Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme

Lewis, Morag A.; Ingham, Neil J.; Chen, Jing; Pearson, Selina; Di Domenico, Francesca; Rekhi, Sohinder; Allen, Rochelle; Drake, Matthew; Willaert, Annelore; Rook, Victoria; Pass, Johanna; Keane, Thomas; Adams, David J.; Tucker, Abigail S.; White, Jacqueline K.; Steel, Karen P.

doi:10.1186/s12915-022-01257-8

Table 1 Summary of the 25 lines found to have a spontaneous mutation affecting hearing

From: Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme

Allele name	Allele symbol	Targeted gene	Line	Phenotype	Mutation	Affected gene(s)	MGI Allele symbol	MGI ID	Mutation type	Mutation effect	Inheri-tance	Parental ES Cell line	Mutation present in parental ES cell line	Mutation type compared to other reported mutant alleles in gene
Stone deaf	stdf	Mms22l	MAKN	Rapidly progressive severe hearing loss	g.9:20967665G > C	S1pr2	S1pr2 < stdf >	MGI:5423977	Missense	T289R	Recessive	JM8.N4	No	Similar
Tikho	Tkh	Rasal2	MEBJ	Progressive hearing loss affecting higher frequencies first	g.6:113759212G > C	Atp2b2	Atp2b2 < Tkh >	MGI:6470863	Missense	R969G	Semi- dominant	JM8A3.N1	No	Hypomorph
Twitch	ttch	Arpc3	MDLY	Complete deafness with vestibular dysfunction	g.16:18584128C > T	Tbx1	Tbx1 < ttch >	MGI:6470864	Missense	D212N	Recessive	JM8A3.N1	No	Hypomorph
Jiggle	jigl	Ccdc122	MEWY	Complete deafness with vestibular dysfunction	Deletion between g.10:74,614,441 and g.10:74,635,149	Pcdh15	Pcdh15 < jigl >	MGI:6470865	Deletion, with potential insertion	Loss of four exons towards 3' end of transcript	Recessive	JM8A1.N3	No	Similar
Rhythm	rthm	Isg20	MFFD	Complete deafness with vestibular dysfunction	g.18:57437258_57740507del	Ctxn3, Ccdc192 and 6 noncoding genes	Del(18Ctxn3-Ccdc192)1Kcl	MGI:6470868	Deletion	303 kb deletion	Recessive	JM8A3.N1	No	N/A
Rhyme	rhme	Rhox13	MEEK	Progressive hearing loss affecting higher frequencies first	g.10:20116294_20153024del	Map3k5, Map7	Del(10Map3k5-Map7)2Kcl	MGI:6470869	Deletion	36.7 kb deletion affecting last 9 exons of Map3k5 and first exon of Map7	Recessive	JM8A3.N1	No	Male sterility of Map7 mutants is the same; hearing loss has not been reported
Spindizzy	spdz	Slc35f2	MHER	Complete deafness with vestibular dysfunction	Disruption between g.4:152,122,586 and g.4:152,123,017	Espn	Espn < spdz >	MGI:6470866	Deletion, with potential insertion or other disruption	Disruption in intron	Recessive	JM8A3.N1	No	Similar
Low frequency	lowf	Mab21l4	MCBX	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8.F6	No	Similar
Low frequency	lowf	Traf3ip3	MATH	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8.N4	No	Similar
Low frequency	lowf	Mad2l2	MBYL	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8.F6	No	Similar
Low frequency	lowf	Kazn	MCFF	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8.N4	No	Similar
Low frequency	lowf	Sesn3	MCKG	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8.N4	No	Similar
Low frequency	lowf	Pabpc1l	MCRU	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8A3.N1	No	Similar
Low frequency	lowf	Kcne2	MCSJ	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8.N4	No	Similar
Low frequency	lowf	Ptpn2	MCTP	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	JM8A3.N1	No	Similar
Low frequency	lowf	Tnfaip1	MDEU	Low frequency hearing loss	g.9:110455454C > A	Klhl18	Klhl18 < lowf >	MGI:6470867	Missense	V55F	Recessive	Unknown (imported line)	Unknown	-
Variable thresholds	vthr	Dusp3	MBVF	Variable moderate to severe hearing loss across all frequencies	Unknown	Unknown	-	-	-	-	-	JM8.N19	Unknown	-
-	Un- known	Pdzd3	METD	Low frequency hearing loss	Unknown	Unknown	-	-	-	-	-	JM8A1.N3	Unknown	-
-	Un- known	Trim66	MCVL	Low frequency hearing loss	Unknown	Unknown	-	-	-	-	-	JM8.N4	Unknown	-
-	Un- known	Tpi1	MCFC	High-frequency hearing loss	Unknown	Unknown	-	-	-	-	-	JM8.N4	Unknown	-
-	Un- known	Aff3	MCND	High-frequency hearing loss	Unknown	Unknown	-	-	-	-	-	JM8.N4	Unknown	-
-	Un- known	Wdtc1	MFYJ	High-frequency hearing loss, only seen in females	Unknown	Unknown	-	-	-	-	-	JM8.N4	Unknown	-
-	Un- known	Ddah1	MGKQ	High-frequency hearing loss	Unknown	Unknown	-	-	-	-	-	JM8A3.N1.C2	Unknown	-
-	Un- known	Mir32	MOAA	High-frequency hearing loss	Unknown	Unknown	-	-	-	-	-	JM8A3	Unknown	-
-	Un- known	Sfxn3	MUBE	Severe & profound hearing loss	Unknown	Unknown	-	-	-	-	-	JM8A3.N1	Unknown	-

This table summarises the 25 lines in which hearing phenotypes were observed which did not segregate with the targeted allele. While some of the targeted genes have been associated with a hearing phenotype (eg Sesn3 homozygotes have abnormal waveforms [11], and ISG20 has been associated with human hearing loss via genome-wide association studies (GWAS) [13, 14]), the targeted alleles did not segregate with the phenotypes reported in this paper and are not linked to the observed hearing loss described here

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ISSN: 1741-7007

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