An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss

Guipponi, Michel; Toh, Min-Yen; Tan, Justin; Park, Daeho; Hanson, Kelly; Ballana, Ester; Kwong, David; Cannon, Ping; Wu, Qingyu; Gout, Alex; Delorenzi, Mauro; Speed, Terence P.; Smith, Richard J.H.; Dahl, Henrik; Petersen, Michael B.; Teasdale, Rohan D.; Estivill, Xavier; Park, Woo Jin; Scott, Hamish S.

doi:10.1002/humu.20617

Cited by 72 publications

(74 citation statements)

References 43 publications

(51 reference statements)

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“…Similarly, in the paper by Finberg et al, none of the anemia was diagnosed at birth. 11 Furthermore, DMT1 patients always had high serum iron values, 8 in contrast with the strikingly low values found in our patient and they developed severe liver iron overload at a young age Sixteen different genes of the TMPRSS family are known in 2008 and mutations in TMPRSS1, 2, 3, and 5 are apparently involved in nonsyndromic deafness 21 and in the pathogenesis of cancers. 22,23 The role of TMPRSS6 in down-regulating hepcidin expression in response to IDA remains to be established.…”

Section: Resultscontrasting

confidence: 59%

Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency

Guillem

Lawson

Kannengiesser

et al. 2008

Blood

115

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Genetic causes of hypochromic microcytic anemia include thalassemias and some rare inherited diseases such as DMT1 deficiency. Here, we show that iron deficiency anemia with poor intestinal absorption and defective iron utilization of IV iron is caused by inherited mutations in TMPRSS6, a liver-expressed gene that encodes a membrane-bound serine protease of previously unknown role that IntroductionHypochromic microcytic anemia is quite common in children with poor iron intake. 1 Genetic causes include thalassemias 2 and some rare inherited forms with defective absorption and use of iron. 3,4 Recently, several groups, 5,6,7 including ours, 7 have reported genetic defects of the iron transporter DMT1 in such patients. It is noteworthy that DMT1 mutations causing microcytic anemia have been associated with rather high serum iron and transferrin saturation as well as increased hepatic iron stores. 8 Here we report the case of a young patient with microcytic iron-refractory iron deficiency anemia (IRIDA) who is a compound heterozygote for 2 nonsense mutations in the transmembrane serine protease TMPRSS6. Mutations in this gene have been recently described in the Mask mouse, a mouse model of IRIDA, 9,10 and TMPRSS6 knock-out mice also display the same phenotype. 11 Our observations confirm a very recent communication reporting germ line mutations of TMPRSS6 in IRIDA patients 12 MethodsThe proband was born to nonconsanguinous English parents and was 18 months old when microcytic hypochromic anemia was first diagnosed. He presented with rotavirus gastroenteritis and he was incidentally found to have a hemoglobin concentration of 60 g/L, mean corpuscular volume of 47 fL, and serum iron below 5 mol/L. He is one of dizygotic twins and has one elder sister. In retrospect, he was thought to be mildly symptomatic of anemia as parents felt he was more lethargic than his twin sister. Both parents are normal and he is the only affected sibling (Table 1). Serum haptoglobin concentration was normal. Thereafter, serum iron was consistently low (Ͻ 5 mol/L), transferrin saturation was less than 5%, and serum ferritin was usually in the lower normal range. Three attempts were undertaken to correct the iron deficiency with 200 mg oral iron per day for either 6 months when he was 21 months old or for 3 months at the age of 3 years and once again at the age of 6 years. He failed to respond to oral iron, with no improvement in hemoglobin levels and serum iron remaining below 5 mol/L. At the age of 7 years, iron absorption was assessed by administration of oral ferrous iron at 3 mg/kg followed by measurement of serum iron at 3 hours. Defective iron absorption was demonstrated by a rise of 13 mol/L in serum iron compared with a minimal expected rise of 18 mol/L for children with comparable IDA. 13 Consequently, he was given a course of intravenous iron (iron sucrose 100 mg weekly during 3 consecutive weeks). Serum ferritin rose from 11 g/L to 109 g/L and hemoglobin rose from 68 g/L before the treatment to a maximum of 98 g/L. Microcytosis ...

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Section: Resultscontrasting

confidence: 59%

Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency

Guillem

Lawson

Kannengiesser

et al. 2008

Blood

115

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“…52,53 Further, TMPRSS5 is coexpressed with hepsin and TMPRSS3 in spiral ganglions of the mouse cochlear, where it is proposed to influence inner ear function. 54 Loss of TMPRSS2 in mice has no effect on development, fertility, survival or organ pathology. 55 However, expression of the androgen regulated TMPRSS2 is up-regulated in high-grade prostate cancer, where it is mislocalized, being expressed in the cytoplasm as well as in the cell membrane.…”

Section: The Type II Transmembrane Serine Proteasesmentioning

confidence: 99%

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

Ramsay¹,

Hooper²,

Folgueras³

et al. 2009

Haematologica

107

104

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Maintaining the body's levels of iron within precise boundaries is essential for normal physiological function. Alterations of these levels below or above the healthy limit lead to a systemic deficiency or overload in iron. The type-two transmembrane serine protease (TTSP), matriptase-2 (also known as TMPRSS6), is attracting significant amounts of interest due to its recently described role in iron homeostasis. The finding of this regulatory role for matriptase-2 was originally derived from the observation that mice deficient in this protease present with anemia due to elevated levels of hepcidin and impaired intestinal iron absorption. Further in vitro analysis has demonstrated that matriptase-2 functions to suppress bone morphogenetic protein stimulation of hepcidin transcription through cell surface proteolytic processing of the bone morphogenetic protein co-receptor hemojuvelin. Consistently, the anemic phenotype of matriptase-2 knockout mice is mirrored in humans with matripase-2 mutations. Currently, 14 patients with iron-refractory iron deficiency anemia (IRIDA) have been reported to harbor various genetic mutations that abrogate matriptase-2 proteolytic activity. In this review, after overviewing the membrane anchored serine proteases, in particular the TTSP family, we summarize the identification and characterization of matriptase-2 and describe its functional relevance in iron metabolism.

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“…The signal was differentially amplified (ϫ10,000) by a Tektronix (TM 503) differential amplifier and digitized (50 kHz sampling rate, with a 12-bit dynamic range and 1024 samples/burst), averaged 512 times, and stored on a computer (Dell Dimensions, Dell Inc., Round Rock, TX). Intensity-amplitude functions of brainstem responses were obtained at each frequency tested (2,4,6,8,10,12,16,20,26, and 32 kHz) by varying the intensities of the tone bursts from 0 to 90 dB SPL, in 5-dB steps. The ABR thresholds were defined as the minimum sound intensity necessary to elicit a clearly distinguishable response.…”

Section: Assessment Of Hearing Functionmentioning

confidence: 99%

“…The coding regions of the Tmprss3 long isoform were PCR-amplified and subcloned into the EYFP-N1 vector (Clontech, Mountain View, CA) using TMPRSS3lSal1-S (5Ј-TTAGTCGACATGGCCGCTTCAGA-AATGGTGGAG-3Ј) and TMPRSS3lBamH1-AS (5Ј-TTAGG-ATCCAAAGTCTTCAGATCTCTCTCCAACTG-3Ј). Plasmid containing the Tmprss3 short isoform tagged with V5 was described previously (8). Plasmids were transfected into HeLa cells using the Lipofectamine LTX Plus transfection reagent (Invitrogen).…”

Section: Cloning Of Tmprss3 Long Isoform and Expression In Hela Cellsmentioning

confidence: 99%

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Tmprss3, a Transmembrane Serine Protease Deficient in Human DFNB8/10 Deafness, Is Critical for Cochlear Hair Cell Survival at the Onset of Hearing

Fasquelle

Scott

Lenoir

et al. 2011

Journal of Biological Chemistry

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Mutations in the type II transmembrane serine protease 3 (TMPRSS3) gene cause non-syndromic autosomal recessive deafness (DFNB8/10), characterized by congenital or childhood onset bilateral profound hearing loss. In order to explore the physiopathology of TMPRSS3 related deafness, we have generated an ethyl-nitrosourea-induced mutant mouse carrying a protein-truncating nonsense mutation in Tmprss3 (Y260X) and characterized the functional and histological consequences of Tmprss3 deficiency. Auditory brainstem response revealed that wild type and heterozygous mice have normal hearing thresholds up to 5 months of age, whereas Tmprss3 Y260X homozygous mutant mice exhibit severe deafness. Histological examination showed degeneration of the organ of Corti in adult mutant mice. Cochlear hair cell degeneration starts at the onset of hearing, postnatal day 12, in the basal turn and progresses very rapidly toward the apex, reaching completion within 2 days. Given that auditory and vestibular deficits often co-exist, we evaluated the balancing abilities of Tmprss3 Y260X mice by using rotating rod and vestibular behavioral tests. Tmprss3 Y260X mice effectively displayed mild vestibular syndrome that correlated histologically with a slow degeneration of saccular hair cells. In situ hybridization in the developing inner ear showed that Tmprss3 mRNA is localized in sensory hair cells in the cochlea and the vestibule. Our results show that Tmprss3 acts as a permissive factor for cochlear hair cells survival and activation at the onset of hearing and is required for saccular hair cell survival. This mouse model will certainly help to decipher the molecular mechanisms underlying DFNB8/10 deafness and cochlear function.

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An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss

Cited by 72 publications

References 43 publications

Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency

Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency

Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

Tmprss3, a Transmembrane Serine Protease Deficient in Human DFNB8/10 Deafness, Is Critical for Cochlear Hair Cell Survival at the Onset of Hearing

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