A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.
To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations.
Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.
Isabelle
I
Meunier
Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.
Béatrice
B
Bocquet
Center for structural biochemistry Montpellier, INSERM U1054-CNRS UMR5048, Montpellier, France.
Gilles
G
Labesse
Sorborne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris. CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC1423, 28 rue de Charenton, 75012 Paris. Institute of Ophthalmology, University College of London, London EC1V 9EL, UK.
Christina
C
Zeitz
Service d'Exploration de la Vision et Neuro-ophtalmologie, Hôpital Robert Salengro, CHU de Lille, France.
Sabine
S
Defoort-Dhellemmes
Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.
Annie
A
Lacroux
Fondation Adolphe de Rothschild, 25 rue Manin, 75019 Paris.
Martine
M
Mauget-Faysse
Service d'Exploration de la Vision et Neuro-ophtalmologie, Hôpital Robert Salengro, CHU de Lille, France.
Isabelle
I
Drumare
Département de pneumologie et d'addictologie. University Hospital Arnaud de Villeneuve, Montpellier, France.
Anne-Sophie
AS
Gamez
Chest and Heart Imaging department, Arnaud de Villeneuve Hospital, Montpellier, France.
Cyril
C
Mathieu
Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.
Virginie
V
Marquette
Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.
Lola
L
Sagot
CHU Lille, Institut de Biochimie et Biologie Moléculaire, F-59000 Lille, France.
Claire-Marie
CM
Dhaenens
Eye clinic, Hôpital Robert Debré, CHRU de Reims, France.
Carl
C
Arndt
Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.
Patrick
P
Carroll
Department of Thoracic Imaging, Hospital Calmette, University Centre of Lille, France.
Martine
M
Remy-Jardin
Ophthalmic center for imaging and laser, rue Antoine Bourdelle, Paris - Department of Ophthalmology, Intercity Hospital and University Paris Est, Créteil, France.
Salomon Yves
SY
Cohen
Sorborne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris. CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC1423, 28 rue de Charenton, 75012 Paris. Institute of Ophthalmology, University College of London, London EC1V 9EL, UK.
José-Alain
JA
Sahel
Service d'Exploration de la Vision et Neuro-ophtalmologie, Hôpital Robert Salengro, CHU de Lille, France.
Bernard
B
Puech
Sorborne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris. CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC1423, 28 rue de Charenton, 75012 Paris. Institute of Ophthalmology, University College of London, London EC1V 9EL, UK.
Isabelle
I
Audo
Fondation Adolphe de Rothschild, 25 rue Manin, 75019 Paris.
Sarah
S
Mrejen
Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.
Christian P
CP
Hamel
D000368:Aged; D001483:Base Sequence; D005190:Family; D005260:Female; D005654:Fundus Oculi; D020022:Genetic Predisposition to Disease; D006801:Humans; D008168:Lung / Q000473:pathology; D008268:Macular Degeneration / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017433:Protein Structure, Secondary; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000235:genetics*; D014057:Tomography, X-Ray Computed
C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3