TY - JOUR
T1 - A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans
AU - Khateb, Samer
AU - Kowalewski, Björn
AU - Bedoni, Nicola
AU - Damme, Markus
AU - Pollack, Netta
AU - Saada, Ann
AU - Obolensky, Alexey
AU - Ben-Yosef, Tamar
AU - Gross, Menachem
AU - Dierks, Thomas
AU - Banin, Eyal
AU - Rivolta, Carlo
AU - Sharon, Dror
N1 - Publisher Copyright:
© 2018, American College of Medical Genetics and Genomics.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Purpose: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome. Methods: Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells. Results: We identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y. Conclusion: Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.
AB - Purpose: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome. Methods: Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells. Results: We identified a homozygous founder missense variant, c.133G>T (p.D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y. Conclusion: Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.
KW - arylsulfatase G
KW - lysosomal storage disease
KW - retinitis pigmentosa
KW - Usher syndrome
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85042758889&partnerID=8YFLogxK
U2 - 10.1038/gim.2017.227
DO - 10.1038/gim.2017.227
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C2 - 29300381
AN - SCOPUS:85042758889
SN - 1098-3600
VL - 20
SP - 1004
EP - 1012
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 9
ER -