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Московский государственный медико-стоматологический университет им. А.И. Евдокимова

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Оториноларингология

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Учебники / Genetics and Auditory Disorders Keats 2002

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Kallmann	XL (AD)	KAL1/	Neural cell	Axonal path-	Occas mild	Hypogonadism; anosmia,		Bick et al. 1992;
syndrome	(AR);	HHA/	adhesion	ﬁnding?	SNHL or	agenesis of olfactory		Legouis et al. 1991
	Xp22.3	KALIG-1/	molecule		mod-severe	lobes
		ADMLX			MHL
Kniest dysplasia	Sporadic,	COL2A1	Collagen a1(II)	Fibrillar	CHL, SNHL,	Skeletal abnormalities;	COL2A1,	Garofalo et al. 1991;
(metatropic	AD;			collagen-	or MHL	cleft palate	Col2a1	Vandenberg et al.
dysplasia, Type II)	12q13.11-			cartilage			transgenic	1991; Winterpacht
	q13.2						knockins;	et al. 1993; Li et al.
							Col2a1 +/-	1995
							heterozygous
							knockout
Krabbe disease	AR;	GALC/	Galactosylcera-	Lysosomal	Progressive	Central nervous system	Twitcher, twi	Sakai et al. 1996;
	14q24.3-	GLD/	mide beta-	enzyme	SNHL	degeneration; progresive		Wenger et al.
	q32.1	GCL	galactosidase			blindness		1997
Marfan syndrome	AD;	MFS1/	Fibrillin-1	Formation of	CHL or	Skeletal, ocular,		Dietz et al. 1991
	15q21.1	MFS/		microﬁbrils	SNHL	cardiovascular anomalies
		FBN1
	3p24.2-p25	MFS2	Unknown	Unknown		Skeletal, cardiovascular		Collod et al. 1994
						anomalies
Marshall syndrome	AD;	COL11A1	Collagen	Fibrillar	Progressive	Skeletal, joint	Chondrodysplasia,	Li et al. 1995; Grifﬁth
	1p21		a1(XI)	collagen-	SNHL	abnormalities; myopia;	cho	et al. 1998; Annunen
				cartilage		cataracts; craniofacial		et al. 1999
						dysmorphism
Mohr-Tranebjaerg	XL;	MTS/	Unknown	Unknown	Progressive	Blindness; dystonia;		Jin et al. 1996
syndrome	Xq22	DDP/			SNHL	mental deﬁciency;
		DFN1				fractures
Multiple synostoses	AD;	SYNS1	Unknown	Unknown	Progressive	Premature joint fusions;		Krakow et al. 1998
syndrome 1	17q21-q22				CHL	skeletal abnormalities
Neuroﬁbromatosis,	AD;	NF2/	MERLIN/	Tumor	Progressive	Schwannomas of other		Rouleau et al. 1993;
Type 2	22q12.2	BANF/	Schwannomin	suppressor	SNHL;	nerves; brain tumors;		Trofatter et al. 1993;
		CAN/			vestibular	cataracts; café-au-lait		Trofatter et al. 1993
		SCH			dysfunction	spots; subcutaneous
						neuroﬁbromas

171 Disorders Auditory Linked-X and Autosomal .6

TABLE 6.5. Continued

	Inheritance	Locus		Gene	Auditory		Mouse	Selected
Syndrome	and Location	Symbol	Gene Product	Function	Phenotype	Associated Pathology	Model	References
Niemann-Pick	AR;	NPC/	Similarity to	Regulation	Progressive	Progressive neurologic	Sphingomyelinosis,	Carstea et al. 1997;
disease, Type C	18q11-q12	NPC1	transmembrane	of intra-	SNHL	deterioration due to	spm	Loftus et al. 1997
			domains,	cellular		sphingomyelin
			cholesterol-	cholesterol		accumulation
			sensing regions	trafﬁcking
Noonan syndrome	AD;	NS1	Unknown	Unknown	Progressive	Skeletal, craniofacial,		Jamieson et al. 1994
	12q24				SNHL or	heart anomalies; mild
					MHL	mental retardation;
						hematologic
						abnormalities;
						lymphangiomas,
						schwannomas
Norrie disease	XLR;	ND/NDP	Homology to	role in	Progressive	Congenital or progressive	NDP -/-	Berger et al. 1992;
	Xp11.4		mucins	neuroectoder-	SNHL	blindness; mental	knock-out	Chen et al. 1992;
				mal cell-cell	(cochlear)	deﬁciency		Meindl et al. 1992;
				interactions?				Berger et al. 1996
Ocular albinism	Xp22.3	OASD	Unknown	Unknown	Late-onset	Ocular albinism		Winship et al.
with sensorineural					progressive			1993
deafness					SNHL
Orofaciodigital	XLD;	OFD1	Unknown	Unknown	Occas CHL	Midfacial clefting;	X-linked	Sweet and Lane 1980;
syndrome, Type 1	Xp22.3-					hyperplasia of oral cavity	polydactyly,	Feather et al. 1997
	p22.2					frenula; cleft tongue;	Xpl
						hand anomalies;
						polycystic kidneys
Osteogenesis	AD (AR);	OI/	Collagen a1(I)	Fibrillar	Progressive	Brittle and deformed	Mov-13,	Bonadio et al. 1990;
imperfecta,Type I,	17q21.31-	COL1A1		collagen-	CHL or	bones, hyperextensible	retroviral	Byers 1993; Pereira
Type II, Type III,	q22.05			bone,	MHL	joints; blue sclerae	insertion into	et al. 1993
Type IV				tendon, skin			col1a1;
							Transgenic

internal deletion of

COL1A1

Friedman .B.T and Grifﬁth .J.A 172

	7q22.1	OI/	Collagen a2(I)	Fibrillar	Same as	Same as above		Byers 1993
		COL1A2		collagen-	above
				bone,
				tendon, skin
Osteopetrosis	AR;	OPTB1	Unknown	Unknown	MHL or	Facial palsy; visual loss;	Osteosclerosis,	Heaney et al. 1998
(Albers-Schönberg	11q12-q13				CHL	generalized osteosclerosis	oc
disease)
Type II	AD;	OPTA2	Unknown	Unknown	CHL	Facial palsy; generalized		Van Hul et al. 1997
	1p21					osteosclerosis
Otopalatodigital	XL;	OPD1	Unknown	Unknown	CHL	Craniofacial, skeletal		Hoar et al. 1992
syndrome, Type I	Xq28					anomalies
Otospondylomega-	AR, AD;	OSMED/	Collagen	Fibrillar	Mod-severe	Skeletal and craniofacial		Vikkula et al. 1995;
epiphyseal	6p21.3	WZS/	a2(XI)	collagen-	SNHL	abnormalities; myopia		Pihlajamaa et al.
dysplasia		COL11A2		cartilage				1998;
Paget disease	AD;	PDB1	Unknown	Unknown	CHL, MHL,	Progressive skull		Fotino et al.
	6p21.3				or SNHL	enlargement; bending of		1977
					(cochlear);	weight-bearing bones;
					vestibular	neurologic deﬁcits
					dysfunction
	18q21-q22	PDB2	Unknown	Unknown				Cody et al. 1997
Pendred syndrome	AR;	PDS	Similarity to	Chloride/	Congenital	Thyroid organiﬁcation		Everett et al. 1997;
	7q31		transmembrane	iodine	SNHL	defect, goiter		Coyle et al. 1998;
			sulfate	transporter?	(cochlear);			Scott et al. 1998
			transporters		vestibular
					dysfunction
Pfeiffer syndrome	AD;	ACS5/	Fibroblast	Tyrosine	CHL	Craniosynostosis; digit		Muenke et al. 1994
	8p11.2-p11.1	FGFR1	growth factor	kinase		abnormalities
			receptor 1	growth
				factor
				receptor
	10q26	ACS5/	Fibroblast	Tyrosine	CHL	Same as above		Lajeunie et al. 1995;
		FGFR2	growth factor	kinase				Rutland et al. 1995
			receptor 2	growth
				factor
				receptor

173 Disorders Auditory Linked-X and Autosomal .6

TABLE 6.5. Continued

	Inheritance	Locus		Gene	Auditory		Mouse	Selected
Syndrome	and Location	Symbol	Gene Product	Function	Phenotype	Associated Pathology	Model	References
	4p16.3	ACS5/	Fibroblast	Tyrosine	CHL	Same as above		Bellus et al. 1996
		FGFR 3	growth factor	kinase
			receptor 3	growth
				factor
				receptor
Piebaldism	AD;	PBT/KIT	KIT	Mast/stem	Progressive	Pigmentation	Dominant	Geissler et al. 1988;
	4q11-q12		protooncogene	cell growth	SNHL	abnormalities; ataxia;	white	Giebel and Spritz
				factor		mental retardation	spotting, W	1991; Spritz and
								Beighton 1998
Refsum disease	AR;	HMSN IV/	Phytanoyl-CoA	Peroxisomal	Progressive	Retinitis pigmentosa		Jansen et al.
	10pter-p11.2	PAHX/	hydroxylase	enzyme	SNHL	(retinal degeneration,		1997; Mihalik et al.
		PHYH				blindness); cerebellar		1997
						ataxia; increased plasma
						phytanic acid
Refsum disease,	AR;	IRD/	Peroxisome	Peroxisomal	Prof SNHL	Retinitis pigmentosa;		Reuber et al. 1997
infantile form	7q21-q22	PEX1	biogenesis	matrix		mental retardation;
			factor 1	protein		craniofacial dysmorphism;
				import		liver dysfunction; short
						stature
Renal tubular	AR;	dRTA/	B1-subunit of	Proton pump	Progressive	Impaired renal tubular		Karet et al. 1999
acidosis with	2cen-q13	ATP6B1	H+-ATPase		SNHL	acid secretion
sensorineural
deafness
Saethre-Chotzen	AD;	SCS/	TWIST	Transcription	Occas CHL	Premature fusion of	Twist +/-	el Ghouzzi et al.
syndrome	7p21	ACS3/		factor	or MHL	cranial sutures; digit	heterozygous	1997; Howard et al.
		TWIST				abnormalities	knockout	1997; Bourgeois et al.
	10q26	SCS/	Fibroblast	Tyrosine	Occas CHL	Same as above	Fgfr2 -/-	1998 Arman et al.
		ACS3/	growth factor	kinase	or MHL		knockout	1998; Paznekas et al.
		FGFR2	receptor 2	growth				1998
				factor
				receptor

Friedman .B.T and Grifﬁth .J.A 174

	4p16.3	SCS/	Fibroblast	Tyrosine	Occas CHL	Same as above	Fgfr3 -/-
		ACS3/	growth factor	kinase	or MHL		knockout
		FGFR3	receptor 3	growth
				factor
				receptor
Sialidosis	AR;	NEU/	Sialidase/	Lysosomal	CHL or	Central nervous system	SM/J line
	6p21.3	NEU1	Neuraminidase	enzyme	MHL	degeneration; vision loss;
						dysostosis; facial
						dysmorphism
Smith-Magenis	Sporadic;	SMS/	Contiguous	Multiple	CHL, occas	Somatic, mental
syndrome	17p11.2	SMCR	gene deletion	deleted genes	SNHL	retardation; behavioral
			including			abnormalities; nonspeciﬁc
			MYO15			combinations of
						anomalies
Spondyloepiphyseal	AD;	SEDC/	Collagen al (II)	Fibrillar	Occas. mod-	Skeletal abnormalities;
dysplasia congenita	12q13.11-	COL2A1		collagen-	severe high-	cleft palate; short stature
	q13.2			cartilage	freq. SNHL
Stickler syndrome,	AD;	STL1/	Collagen a1(II)	Fibrillar	Progressive	Skeletal and joint	COL2A1,
Type I	12q13.11-	COL2A1		collagen-	SNHL, occas	abnormalities;	Col2a1
	q13.2			cartilage	CHL	myopia; cataracts;	transgenic
						craniofacial dysmorphism	knockins;
							Col2a1 +/-
							heterozygous
							knockout
Type II	AD;	STL2/	Collagen	Fibrillar	SNHL	Same as type I Stickler’s
	6p21.3	COL11A2	a2(XI)	collagen-		syndrome, but no ocular
				cartilage		manifestations
Type III	AD;	STL3/	Collagen	Fibrillar	SNHL	Same as type I Stickler’s	Chondrodys-
	1p21	COL11A1	a1(XI)	collagen-		syndrome	plasia, cho
				cartilage
Symphalangism,	AD;	SYM1	Unknown	Unknown	CHL	Fusion of extremity joints
proximal	17q21-q22
Tay-Sachs disease	AR;	TSD/	Hexosaminidase	Lysosomal	SNHL	Progressive mental, motor	Hexa -/-
	15q23-q24	HEXA	A	enzyme		retardation; seizures;	knockout
						blindness

Colvin et al. 1996; Deng et al. 1996; Paznekas et al. 1998

Bonten et al. 1996; Pshezhetsky et al. 1997; Rottier et al. 1998

Chen et al. 1997; Smith et al. 1986

Garofalo et al. 1991; Vandenberg et al. 1991; Spranger et al. 1994; Li et

al. 1995

Vikkula et al. 1995; Sirko-Osadsa et al. 1998

Li et al. 1995; Richards et al. 1996; Annunen et al. 1999

Polymeropoulos et al. 1995

Sango et al. 1995; Myerowitz 1997

175 Disorders Auditory Linked-X and Autosomal .6

TABLE 6.5. Continued

	Inheritance	Locus		Gene	Auditory		Mouse	Selected
Syndrome	and Location	Symbol	Gene Product	Function	Phenotype	Associated Pathology	Model	References
Tietz syndrome	AD;	MITF	Microphthalmia	Transcription	Congenital	Skin/hair albinism	microphthal-	Steingrimsson et al.
	3p14.1-p12.3		-associated	factor	prof SNHL;		mia, mi	1994; Amiel et al.
			transcription		normal			1998; Smith et al.
			factor		vestibular			1997
					function
Townes-Brocks	AD;	TBS/	C2H2 zinc	Transcription	SNHL	Deformities of external		Kohlhase et al. 1998
syndrome	16q12.1	SALL1	ﬁnger	factor		ears, anus, digits, kidneys,
			transcription			and heart
			factor
Treacher Collins’	AD;	TCOF1/	Nucleolar	Nucleolar	Variable	Craniofacial anomalies;		Treacher Collins,
syndrome	5q32-q33.1	TCS/	phosphoprotein	protein	CHL	eyelid colobomas		syndrome
		MFD1		trafﬁcking?				collaborative group
								1996; Wise et al. 1997
Usher syndrome,	AR;	USH1A/	Unknown	Unknown	Congenital	Onset of retinitis		Kaplan et al. 1992
Type 1A	14q32	USH1			severe-prof	pigmentosa (retinal
					SNHL;	degeneration, blindness)
					absent	by 10 yrs
					vestibular
					function
Type 1B	11q13.5	USH1B/	Type VIIA	Intracellular	Same as	Same as above	shaker-1, sh1	Gibson et al. 1995;
		MYO7A	myosin-	actin-based	above			Weil et al. 1995
			unconventional	transport?
Type 1C	11p15.1	USH1C	Unknown	Unknown	Same as	Same as above		Keats et al. 1994
					above
Type 1D	10q	USH1D	Unknown	Unknown	Same as	Same as above		Wayne et al. 1996
					above
Type 1E	21q21	USH1E	Unknown	Unknown	Same as	Same as above		Chaib et al. 1997
					above
Type 1F	10	USH1F	Unknown	Unknown	Same as	Same as above		Wayne et al. 1997
					above

Friedman .B.T and Grifﬁth .J.A 176

Type 2A	AR;	USH2A	Contains	Extracellular	Congenital	Onset of retinitis		Eudy et al. 1998
	1q41		laminin-EGF	matrix/	mod-severe	pigmentosa in late
			and ﬁbronectin	adhesion	SNHL;	teens/early adulthood
			domains	molecule?	normal
					vestibular
					function
Type 2B	5q14.3-q21.3	USH2B	Unknown	Unknown	Same as	Same as above		Pieke-Dahl et al. 1993;
					above			Pieke-Dahl et al. 1998
Type 3	AR;	USH3	Unknown	Unknown	Progressive	Variable onset of retinitis		Sankila et al. 1995
	3q21-q25				SNHL;	pigmentosa
					normal or
					decreased
					vestibular
					function
Van Buchem disease AR;		VBCH	Unknown	Unknown	MHL or	Skeletal hyperostosis		Van Hul et al. 1998
	17q11.2				SNHL
Velocardiofacial	AD;	VCFS	Frequent	Multiple	CHL (assoc	Heart anomalies; facial		Driscoll et al. 1992
(Shprintzen)	22q11		contiguous gene	deleted	w/otitis	dysmorphism; palatal
syndrome			deletion	genes	media),	cleft/dysfunction; mild
					occas SNHL	mental retardation
Vohwinkel	13q12	KHM/	Gap junction	Gap junction	SNHL	Mutilating keratoderma		Maestrini et al. 1999
syndrome, classic		GJB2/	beta-2 subunit	subunit
form		CX26
Vohwinkel	AD;	LOR	loricrin	Structural	Congenital	Hyperkeratosis and other		Maestrini et al. 1996
syndrome, variant	1q21			component	and/or	skin anomalies
form				of cell	progressive
				envelope of	SNHL
				epidermis
Waardenburg	AD;	WS1/	Paired-box	Transcription	Occas	Craniofacial dysmorphism,	splotch, sp	Epstein, Vekemans,
syndrome, Type I	2q35	PAX3	DNA-binding	factor	congenital,	including dystopia		and Gros 1991;
			protein		variable	canthorum; pigmentation		Baldwin et al. 1992;
					SNHL	abnormalities		Tassabehji et al. 1992
Type II	AD;	WS2/	Microphthalmia	Transcription	Same as	Craniofacial dysmorphism	microphthal-	Steingrimsson et al.
	3p14.1-p12.3	WS2A/	-associated	factor	WS1, SNHL	without dystopia	mia, mi	1994; Tassabehji,
		MITF	transcription		may be	canthorum; pigmentation		Newton, and Read
			factor		progressive	abnormalities		1994

177 Disorders Auditory Linked-X and Autosomal .6

TABLE 6.5. Continued

	Inheritance	Locus		Gene	Auditory		Mouse	Selected
Syndrome	and Location	Symbol	Gene Product	Function	Phenotype	Associated Pathology	Model	References
Type II,	Autosomal	WS2-OA/	Microphthalmia	Transcription	Progressive	Ocular albinism		Bard, 1978; Morell
with ocular	digenic;	MITF	-associated	factor	SNHL			et al. 1997
albinism	3p14.1-		transcription
	p12.3		factor
	11q14-q21	OCA1/	Tyrosinase	Tyrosinase
		TYR
Type III (Klein-	AD, AR;	WS3/	Paired-box	Transcription	SNHL	Same as WS1, with	splotch, sp	Epstein et al.
Waardenburg)	2q35	PAX3	DNA-binding	factor		skeletal abnormalties		1991; Hoth et al.
			protein					1993; Zlotogora et al.
								1995
Type IV (Shah-	AR;	WS4/	Endothelin-3	Extracellular	SNHL	Same as WS2, with	Spotting	Baynash et al. 1994;
Waardenburg)	20q13.2-	EDN3		signalling		Hirschsprung disease	lethal, sl;	Edery et al. 1996;
	q13.3			peptide		(lack of autonomic	edn3 -/-	Hofstra et al. 1996
						innervation to colon)	knock-out
	AR; 13q22	WS4/	Endothelin	G	SNHL	Same as above	ednrb -/-	Hosoda et al. 1994;
		EDNRB	receptor, type B	proteincoupled			knock-out	Puffenberger et al.
				receptor				1994; Attie et al. 1995
	AD; 22q13	WS4/	SRY-related	Transcription	SNHL	Same as above	Dominant	Herbarth et al. 1998;
		SOX10	transcription	factor			megacolon,	Pingault et al. 1998;
			factor				Dom	Southard-Smith et al.
								1998
Wolfram syndrome	AR;	WFS/	Wolframin	Unknown	Progressive	Progressive blindness,		Inoue et al. 1998;
	4p16.1	WFS1c			SNHL,	diabetes mellitus, diabetes		Strom et al. 1998
					HF > LF	insipidus
Xeroderma	AR;	XPA/	Zinc ﬁnger	DNA	Progressive	Photosensitivity;	Xpa -/-	Tanaka et al. 1990; de
pigmentosum,	9q22.3-q31	XP1/	domain protein	excision	SNHL,	cutaneous malignancies;	knock-out	Vries et al. 1995;
group A		XPAC		repair	HF > LF	neurologic abnormalities		Nakane et al. 1995

Friedman .B.T and Grifﬁth .J.A 178

6. Autosomal and X-Linked Auditory Disorders

179

A possible pitfall to this line of associative reasoning is that a syndrome may be caused by a contiguous gene deletion, or by linked mutations in separate genes. In this circumstance, a hearing loss gene may be altered in association with a separate gene(s) causing pathology in another organ system. This was observed in a kindred originally used to identify DFNB1 (Kelsell et al. 1997) in which autosomal dominant palmoplantar keratoderma (PPK) was also segregating. Clinical ascertainment of that pedigree identiﬁed 3 individuals with PPK but without hearing loss, and linkage of

GJB2 was demonstrated with the hearing loss phenotype but not the PPK phenotype. This kindred illustrates how contiguous gene deletions or co-segregation of mutations have the potential to confound the linkage analysis and any conclusions regarding shared pathogenetic mechanisms between the affected organ systems.

Approximately 100 genes for syndromic hearing loss have now been mapped, and over 60 of these have been identiﬁed (Table 6.5). Some of these genes and their corresponding mutations have provided interesting and novel insights into the development and function of the auditory system. The following review will focus on six forms of syndromic hearing loss in which at least some of the causative genes have been identiﬁed, and the resulting molecular data has raised and/or answered important questions regarding the molecular basis of auditory function and hearing impairment. A discussion of all forms of syndromic hearing loss (Gorlin et al. 1995) in which the genes have been mapped or identiﬁed would require its own volume. Table 6.5 summarizes some of the essential features of approximately 100 forms of syndromic hearing loss.

It is clinically important to identify the cause of hearing loss in families where in auditory dysfunction is accompanied by other serious problems, such as heart conduction problems (Jervell and Lange-Nielsen syndrome), progressive nephritis (Alport syndrome), or progressive loss of vision

(Usher syndrome). Within the congenitally hearing impaired population, the incidences of these three syndromes are estimated to be 0.25%, 1.0%, and 3 to 8%, respectively (Gorlin et al. 1995; Vernon 1959). Hearing loss may be detected before manifestation of other organ system pathologies in all three of these syndromes. For example, the hearing loss in Jervell and Lange–Nielsen syndrome may be evident before the onset of fainting attacks or detection of a cardiac arrhythmia. Life-saving anti-arrhythmic therapy may thus be initiated prophylactically (Ackerman 1998).

5.1 Stickler Syndrome

5.1.1 Phenotype

Stickler syndrome (OMIM 108300, 184840) is an autosomal-dominant disorder characterized by progressive sensorineural hearing loss, skeletal dysplasia, craniofacial dysmorphism, cataracts, and myopia. Marshall syndrome

180 A.J. Grifﬁth and T.B. Friedman

(OMIM 154780) has a similar phenotype, but may be distinguished by a more severe degree of hearing loss and its unique pattern of craniofacial dysmorphism persisting into adulthood (Annunen et al. 1999; Ayme and Preus 1984; Marshall 1958) (Fig. 6.5). The sensorineural hearing loss in these disorders begins during early childhood and progresses over the ensuing decades. The hearing loss is occasionally mixed (Lucarini et al. 1987) and may be due to otitis media or its sequelae, especially in affected children.

Given the characteristic skeletal abnormalities, it is reasonable to postulate that the sensorineural hearing loss might be associated with gross morphogenetic abnormalities of the inner ear. However, there are no reports of temporal bone histopathology for these disorders, although computed tomography (CT) scans of temporal bones of 19 Stickler’s syndrome patients and three Marshall syndrome patients have revealed no abnormalities (Grifﬁth et al. 2000b; Szymko et al. 2000). Therefore, the bony anatomy of the inner ear is at least grossly normal in these disorders.

FIGURE 6.5. Frontal and side views of an individual affected with Marshall syndrome (Grifﬁth et al. 1998). These facial features persisting into adulthood are characteristic of Marshall syndrome and include severe midfacial growth deﬁciency, a small upturned nose, and a prominent forehead. (Reprinted from Grifﬁth et al.,The American Journal of Human Genetics, Copyright 1998, with permission of The University of Chicago Press.)

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