Specific alleles of CLN7/MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy

NIHR BioResource-Rare Diseases, UK Inherited Retinal Disease Consortium

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

Original languageEnglish (US)
Pages (from-to)2906-2914
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number7
DOIs
StatePublished - Jun 1 2017

Fingerprint

Retinal Dystrophies
Presynaptic Terminals
Alleles
Mutation
Retinal Diseases
Proteins
Retina
Light Signal Transduction
Exome
Electroretinography
Retinitis Pigmentosa
Electrophysiology
Fluorescence Microscopy
Confocal Microscopy
Synapses
Genome
DNA

Keywords

  • DNA sequencing
  • Electroretinography
  • Immunohistology
  • Macular degeneration
  • Photoreceptor synapse
  • Retinal dystrophy

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Specific alleles of CLN7/MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy. / NIHR BioResource-Rare Diseases; UK Inherited Retinal Disease Consortium.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 7, 01.06.2017, p. 2906-2914.

Research output: Contribution to journalArticle

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title = "Specific alleles of CLN7/MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy",
abstract = "PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.",
keywords = "DNA sequencing, Electroretinography, Immunohistology, Macular degeneration, Photoreceptor synapse, Retinal dystrophy",
author = "{NIHR BioResource-Rare Diseases} and {UK Inherited Retinal Disease Consortium} and Khan, {Kamron N.} and El-Asrag, {Mohammed E.} and Ku, {Cristy A.} and Holder, {Graham E.} and Martin McKibbin and Gavin Arno and Poulter, {James A.} and Keren Carss and Tejaswi Bommireddy and Saghar Bagheri and Benjamin Bakall and Scholl, {Hendrik P.} and Raymond, {F. Lucy} and Carmel Toomes and Inglehearn, {Chris F.} and Mark Pennesi and Moore, {Anthony T.} and Michel Michaelides and Webster, {Andrew R.} and Manir Ali",
year = "2017",
month = "6",
day = "1",
doi = "10.1167/iovs.16-20608",
language = "English (US)",
volume = "58",
pages = "2906--2914",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "7",

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TY - JOUR

T1 - Specific alleles of CLN7/MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy

AU - NIHR BioResource-Rare Diseases

AU - UK Inherited Retinal Disease Consortium

AU - Khan, Kamron N.

AU - El-Asrag, Mohammed E.

AU - Ku, Cristy A.

AU - Holder, Graham E.

AU - McKibbin, Martin

AU - Arno, Gavin

AU - Poulter, James A.

AU - Carss, Keren

AU - Bommireddy, Tejaswi

AU - Bagheri, Saghar

AU - Bakall, Benjamin

AU - Scholl, Hendrik P.

AU - Raymond, F. Lucy

AU - Toomes, Carmel

AU - Inglehearn, Chris F.

AU - Pennesi, Mark

AU - Moore, Anthony T.

AU - Michaelides, Michel

AU - Webster, Andrew R.

AU - Ali, Manir

PY - 2017/6/1

Y1 - 2017/6/1

N2 - PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

AB - PURPOSE. Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. METHODS. Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. RESULTS. Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. CONCLUSIONS. This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease.

KW - DNA sequencing

KW - Electroretinography

KW - Immunohistology

KW - Macular degeneration

KW - Photoreceptor synapse

KW - Retinal dystrophy

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JO - Investigative Ophthalmology and Visual Science

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