TY - JOUR
T1 - Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6
AU - Ratbi, Ilham
AU - Falkenberg, Kim D.
AU - Sommen, Manou
AU - Al-Sheqaih, Nada
AU - Guaoua, Soukaina
AU - Vandeweyer, Geert
AU - Urquhart, Jill E.
AU - Chandler, Kate E.
AU - Williams, Simon G.
AU - Roberts, Neil A.
AU - El Alloussi, Mustapha
AU - Black, Graeme C.
AU - Ferdinandusse, Sacha
AU - Ramdi, Hind
AU - Heimler, Audrey
AU - Fryer, Alan
AU - Lynch, Sally-Ann
AU - Cooper, Nicola
AU - Ong, Kai Ren
AU - Smith, Claire E. L.
AU - Inglehearn, Christopher F.
AU - Mighell, Alan J.
AU - Elcock, Claire
AU - Poulter, James A.
AU - Tischkowitz, Marc
AU - Davies, Sally J.
AU - Sefiani, Abdelaziz
AU - Mironov, Aleksandr A.
AU - Newman, William G.
AU - Waterham, Hans R.
AU - van Camp, Guy
PY - 2015
Y1 - 2015
N2 - Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6
AB - Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6
U2 - https://doi.org/10.1016/j.ajhg.2015.08.011
DO - https://doi.org/10.1016/j.ajhg.2015.08.011
M3 - Article
C2 - 26387595
SN - 0002-9297
VL - 97
SP - 535
EP - 545
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -