De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment

被引：72

作者：

Hempel, Maja ^{[1
]}

Cremer, Kirsten ^{[2
]}

Ockeloen, Charlotte W. ^{[3
]}

Lichtenbelt, Klaske D. ^{[4
]}

Herkert, Johanna C. ^{[5
]}

Denecke, Jonas ^{[6
]}

Haack, Tobias B. ^{[7
,8
]}

Zink, Alexander M. ^{[2
]}

Becker, Jessica ^{[2
]}

Wohlleber, Eva ^{[2
]}

Johannsen, Jessika ^{[6
]}

Alhaddad, Bader ^{[8
]}

Pfundt, Rolph ^{[3
]}

Fuchs, Sigrid ^{[1
]}

Wieczorek, Dagmar ^{[9
]}

Strom, Tim M. ^{[7
,8
]}

van Gassen, Koen L. I. ^{[4
]}

Kleefstra, Tjitske ^{[3
]}

Kubisch, Christian ^{[1
]}

Engels, Hartmut ^{[2
]}

Lessel, Davor ^{[1
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany

[2] Univ Bonn, Inst Human Genet, D-53127 Bonn, Germany

[3] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[4] Univ Med Ctr Utrecht, Dept Med Genet, NL-3508 GA Utrecht, Netherlands

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[6] Univ Med Ctr Eppendorf, Dept Pediat, D-20246 Hamburg, Germany

[7] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[8] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany

[9] Univ Duisburg Essen, Univ Klinikum Essen, Inst Human Genet, D-45122 Essen, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2015年 / 97卷 / 03期

关键词：

KIF5C;

D O I：

10.1016/j.ajhg.2015.08.003

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.

引用

页码：493 / 500

页数：8