Table 2.

Disease related human point mutations: effect on protease function

Protease	Mutation	Location	Phenotype	Effect on function in vitro	Refs
Type II
TMPRSS3	R216L	SPD- zymogen activation site	Non-syndromic autosomal recessive deafness	Mutant does not undergo proteolytic processing representative of auto-activation.	[178]
	P404L	SPD		Mutant does not undergo proteolytic processing representative of auto-activation. Catalytically inactive.	[80,177]
	D103G,R109W	LDLRA		These mutants do not undergo proteolytic processing representative of auto-activation and are unable to activate ENaC substrate compared to WT.	[80]
	C194F	SRCR
	W215C	SPD
TMPRSS5	A317S	SPD	Nonsyndromic deafness	Serine protease domain is catalytically inactive	[40]
Matriptase	G827R	SPD	Impaired epidermal barrier function, icthyosis, hypertrichosis, follicular atrophoderma, corneal opacity and photophobia	Mutation is in active site binding cleft. Serine protease domain is catalytically inactive and protease unable to auto-activate.	[103,170,172]
Matriptase-2	A118D	SEA	IRIDA	Mutant protein reaches cell surface and is shed, but is unable to become activated.	[1]
	D521N	LDLRA	IRIDA	LDLRA mutants cannot not reach cell surface, are retained in Golgi and cannot activate. CUB mutant has reduced activation. Mutants are still able to interact with hemojuvelin and partially repressed hepcidin expression.	[75]
	E552K	LDLRA
	G442R	CUB-2
Corin	T555I/Q568P	Frizzled-like domain-2	Decreased processing of pro-atrial natriurectic peptide resulting in hypertension and cardiac hypertrophy.	Mutant reaches cell surface, but possesses impaired catalytic activity due to impaired zymogen activation.	[78,79]