TY - JOUR
T1 - Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency
AU - NISC Comparative Sequencing Program
AU - Stephen, Joshi
AU - Vilboux, Thierry
AU - Mian, Luhe
AU - Kuptanon, Chulaluck
AU - Sinclair, Courtney M.
AU - Yildirimli, Deniz
AU - Maynard, Dawn M.
AU - Bryant, Joy
AU - Fischer, Roxanne
AU - Vemulapalli, Meghana
AU - Mullikin, James C.
AU - Huizing, Marjan
AU - Gahl, William A.
AU - Malicdan, May Christine V.
AU - Gunay-Aygun, Meral
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg (outside the USA).
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts.
AB - Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic “molar tooth sign” on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients’ fibroblasts.
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U2 - 10.1007/s00439-017-1765-z
DO - 10.1007/s00439-017-1765-z
M3 - Article
C2 - 28220259
AN - SCOPUS:85013159174
SN - 0340-6717
VL - 136
SP - 399
EP - 408
JO - Human genetics
JF - Human genetics
IS - 4
ER -