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Mutations in CDK5RAP2 cause Seckel syndrome.

Yigit G, Brown KE, Kayserili H, Pohl E, Caliebe A, Zahnleiter D, Rosser E, Bögershausen N, Uyguner ZO, Altunoglu U, Nürnberg G, Nürnberg P, Rauch A, Li Y, Thiel CT, Wollnik B - Mol Genet Genomic Med (2015)

Bottom Line: CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly.Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152.This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Cologne Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany.

ABSTRACT
Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

No MeSH data available.


Related in: MedlinePlus

Clinical and molecular findings in family SK-2 with Seckel syndrome. (A) Pedigree of the consanguineous family from Pakistan, front and lateral photographs and MRI images of the affected individual IV.2 at the age of 3 years. (B) Parametric linkage analysis of family SK-2. LOD scores were calculated with ALLEGRO, and the highest scores were obtained for markers on chromosomes 7 and 9. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (III.6 and IV.2) compared with heterozygous carrier (II.3, III.2, and III.3) and wild-type sequences (IV.1).
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fig02: Clinical and molecular findings in family SK-2 with Seckel syndrome. (A) Pedigree of the consanguineous family from Pakistan, front and lateral photographs and MRI images of the affected individual IV.2 at the age of 3 years. (B) Parametric linkage analysis of family SK-2. LOD scores were calculated with ALLEGRO, and the highest scores were obtained for markers on chromosomes 7 and 9. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (III.6 and IV.2) compared with heterozygous carrier (II.3, III.2, and III.3) and wild-type sequences (IV.1).

Mentions: The index patient of the Pakistani family SK-2 (IV.2 in Fig.2A) is the second child of healthy first degree cousins. She was born at term via spontaneous delivery after an uneventful pregnancy. Her birth weight was 2160 g. When she was clinically investigated at 25 months of age, her parents had no concerns about her development. She was microcephalic (−6.2 SD) and had short stature (−5 SD). In addition to her typical facial appearance, her skeletal survey showed signs consistent with the clinical diagnosis of Seckel syndrome, such as mild bowing of the radius and an unusual slope to the radial head, pseudo-epiphyses of the second metacarpals and a mild chevron deformity of the lower end of the femora. Her motor skills were age-appropriate but her attention and language skills were delayed. MRI of the brain at 32 months was normal. The family pedigree showed multiple loops of consanguinity and one paternal aunt was reported to have short stature and to show pointed teeth and child-like behavior. She was not clinically investigated. No mutation in PCNT was found in the index patient. She carried a heterozygous SNP in PCNT, excluding homozygosity for this gene and thus making a diagnosis of MOPD II unlikely in this family.


Mutations in CDK5RAP2 cause Seckel syndrome.

Yigit G, Brown KE, Kayserili H, Pohl E, Caliebe A, Zahnleiter D, Rosser E, Bögershausen N, Uyguner ZO, Altunoglu U, Nürnberg G, Nürnberg P, Rauch A, Li Y, Thiel CT, Wollnik B - Mol Genet Genomic Med (2015)

Clinical and molecular findings in family SK-2 with Seckel syndrome. (A) Pedigree of the consanguineous family from Pakistan, front and lateral photographs and MRI images of the affected individual IV.2 at the age of 3 years. (B) Parametric linkage analysis of family SK-2. LOD scores were calculated with ALLEGRO, and the highest scores were obtained for markers on chromosomes 7 and 9. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (III.6 and IV.2) compared with heterozygous carrier (II.3, III.2, and III.3) and wild-type sequences (IV.1).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585455&req=5

fig02: Clinical and molecular findings in family SK-2 with Seckel syndrome. (A) Pedigree of the consanguineous family from Pakistan, front and lateral photographs and MRI images of the affected individual IV.2 at the age of 3 years. (B) Parametric linkage analysis of family SK-2. LOD scores were calculated with ALLEGRO, and the highest scores were obtained for markers on chromosomes 7 and 9. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (III.6 and IV.2) compared with heterozygous carrier (II.3, III.2, and III.3) and wild-type sequences (IV.1).
Mentions: The index patient of the Pakistani family SK-2 (IV.2 in Fig.2A) is the second child of healthy first degree cousins. She was born at term via spontaneous delivery after an uneventful pregnancy. Her birth weight was 2160 g. When she was clinically investigated at 25 months of age, her parents had no concerns about her development. She was microcephalic (−6.2 SD) and had short stature (−5 SD). In addition to her typical facial appearance, her skeletal survey showed signs consistent with the clinical diagnosis of Seckel syndrome, such as mild bowing of the radius and an unusual slope to the radial head, pseudo-epiphyses of the second metacarpals and a mild chevron deformity of the lower end of the femora. Her motor skills were age-appropriate but her attention and language skills were delayed. MRI of the brain at 32 months was normal. The family pedigree showed multiple loops of consanguinity and one paternal aunt was reported to have short stature and to show pointed teeth and child-like behavior. She was not clinically investigated. No mutation in PCNT was found in the index patient. She carried a heterozygous SNP in PCNT, excluding homozygosity for this gene and thus making a diagnosis of MOPD II unlikely in this family.

Bottom Line: CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly.Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152.This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

View Article: PubMed Central - PubMed

Affiliation: Institute of Human Genetics, University of Cologne Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne Cologne, Germany.

ABSTRACT
Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice-site mutations c.383+1G>C and c.4005-9A>G in CDK5RAP2 in two consanguineous families with Seckel syndrome. CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK5RAP2 as a disease-causing gene for Seckel syndrome and show that loss of functional CDK5RAP2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK5RAP2 and CEP152. This finding points toward a potential additive genetic effect of mutations in CDK5RAP2 and CEP152.

No MeSH data available.


Related in: MedlinePlus