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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 the Turkish family SK-1 with Seckel syndrome. (A) Pedigree, front and side views of affected individuals II.1 and II.3 at ages 19 and 10 years, respectively, showing the typical sloping forehead, beaked nose with pointed tip, midface hypoplasia, and microretrognathia. (B) Parametric linkage analysis of the family SK-1 with 20,044 selected SNP markers from the Affymetrix Sty array. LOD scores calculated with ALLEGRO are given along the y axis relative to genomic position in cM (centi Morgan) on the x axis. The highest scores were obtained for markers on chromosomes 1, 9, 15 and 18. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (II.1 and II.3) compared with heterozygous carrier sequences (I.1, I.2 and II.2).
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fig01: Clinical and molecular findings in the Turkish family SK-1 with Seckel syndrome. (A) Pedigree, front and side views of affected individuals II.1 and II.3 at ages 19 and 10 years, respectively, showing the typical sloping forehead, beaked nose with pointed tip, midface hypoplasia, and microretrognathia. (B) Parametric linkage analysis of the family SK-1 with 20,044 selected SNP markers from the Affymetrix Sty array. LOD scores calculated with ALLEGRO are given along the y axis relative to genomic position in cM (centi Morgan) on the x axis. The highest scores were obtained for markers on chromosomes 1, 9, 15 and 18. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (II.1 and II.3) compared with heterozygous carrier sequences (I.1, I.2 and II.2).

Mentions: We have clinically assessed two consanguineous families of Turkish and Pakistani ancestry with two individuals in each family diagnosed with a mild form of Seckel syndrome. The index patient of the Turkish family SK-1 (II.1 in Fig.1A) is the first child born to healthy second degree cousins. He was born at term by uncomplicated spontaneous delivery. His birth weight was 2200 g, the birth length and head circumference were not documented. He walked at 13 months of age and spoke his first words at 12 months. He was referred to our clinic at 9 years of age where he was noted to have microcephaly (−4 SD) with a sloping forehead, beaked nose, and midface hypoplasia. Additionally, he had short stature (−3.2 SD) accompanied by skeletal findings such as delayed bone age, fifth finger clinodactyly, and absence of the twelfth ribs. Cognitive impairment was mild-to-moderate (Table1). The patient’s youngest sister (II.3 in Fig.1A), the third child of this family, also presented with Seckel syndrome. She had microcephaly and hip dislocation as a newborn. A cranial MRI from that time did not show any severe structural abnormalities. Achievement of motor milestones was within the normal range, but a mild cognitive impairment became obvious at school age. When we saw her at age 10, she had microcephaly (−4 SD), dysmorphic facial features very similar to those seen in her brother, and short stature (−3.4 SD) (Fig.1A, Table1).


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 the Turkish family SK-1 with Seckel syndrome. (A) Pedigree, front and side views of affected individuals II.1 and II.3 at ages 19 and 10 years, respectively, showing the typical sloping forehead, beaked nose with pointed tip, midface hypoplasia, and microretrognathia. (B) Parametric linkage analysis of the family SK-1 with 20,044 selected SNP markers from the Affymetrix Sty array. LOD scores calculated with ALLEGRO are given along the y axis relative to genomic position in cM (centi Morgan) on the x axis. The highest scores were obtained for markers on chromosomes 1, 9, 15 and 18. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (II.1 and II.3) compared with heterozygous carrier sequences (I.1, I.2 and II.2).
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Related In: Results  -  Collection

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fig01: Clinical and molecular findings in the Turkish family SK-1 with Seckel syndrome. (A) Pedigree, front and side views of affected individuals II.1 and II.3 at ages 19 and 10 years, respectively, showing the typical sloping forehead, beaked nose with pointed tip, midface hypoplasia, and microretrognathia. (B) Parametric linkage analysis of the family SK-1 with 20,044 selected SNP markers from the Affymetrix Sty array. LOD scores calculated with ALLEGRO are given along the y axis relative to genomic position in cM (centi Morgan) on the x axis. The highest scores were obtained for markers on chromosomes 1, 9, 15 and 18. (C) Electropherograms of the identified homozygous CDK5RAP2 mutation (II.1 and II.3) compared with heterozygous carrier sequences (I.1, I.2 and II.2).
Mentions: We have clinically assessed two consanguineous families of Turkish and Pakistani ancestry with two individuals in each family diagnosed with a mild form of Seckel syndrome. The index patient of the Turkish family SK-1 (II.1 in Fig.1A) is the first child born to healthy second degree cousins. He was born at term by uncomplicated spontaneous delivery. His birth weight was 2200 g, the birth length and head circumference were not documented. He walked at 13 months of age and spoke his first words at 12 months. He was referred to our clinic at 9 years of age where he was noted to have microcephaly (−4 SD) with a sloping forehead, beaked nose, and midface hypoplasia. Additionally, he had short stature (−3.2 SD) accompanied by skeletal findings such as delayed bone age, fifth finger clinodactyly, and absence of the twelfth ribs. Cognitive impairment was mild-to-moderate (Table1). The patient’s youngest sister (II.3 in Fig.1A), the third child of this family, also presented with Seckel syndrome. She had microcephaly and hip dislocation as a newborn. A cranial MRI from that time did not show any severe structural abnormalities. Achievement of motor milestones was within the normal range, but a mild cognitive impairment became obvious at school age. When we saw her at age 10, she had microcephaly (−4 SD), dysmorphic facial features very similar to those seen in her brother, and short stature (−3.4 SD) (Fig.1A, Table1).

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