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Genetics of Dwarfism« Back to Volume 24, Issue 2, November 2008 - Table of Contents The centrosome is a cytoplasmic organelle that prepares the mitotic spindle for chromosome segregation and also regulates progression of the cell cycle through mitosis.1 Pericentrin 2 (PCNT2) is a centrosomal protein that is essential for the integrity of the mitotic spindle as it links the microtubules of the mitotic spindle apparatus to the centrosomal core. PCNT2 is also involved in the process of normal cell division at the G2-M checkpoint. Thus, loss of PCNT2 likely results in cell death because of defects in both chromosome segregation and mitosis. Rauch et al and Griffith et al have described clinical syndromes associated with biallelic loss-of-function mutations in the gene encoding PCNT2—also termed kendrin (PCNT2 - chromosome 21q22.3-qter - OMIM 605925). Microcephalic osteodysplastic primordial dwarfism (MOPD) is characterized by intrauterine and postnatal growth retardation, short limbs (brachymelia), and microcephaly (Figure 1). The humeri and femora are broad, shortened, and bowed. Clinically, MOPD has been subclassified into types I (OMIM 210710), II (OMIM 210720), and III (OMIM 210730). Types I and III are considered to be variations of the same disorder and are associated with dysplasia of the skull, vertebrae, and limbs and malformations of the brain and early death; no gene mutation has as yet been identified in these subjects. In patients with MOPD II, an autosomal recessive disorder, facial features are similar to those of patients with Seckel syndrome (vide infra); birth weight is <1.5 kg at term; average adult height is 100 cm; adult head circumference is 40 cm, mentation is reasonably normal. Adults with MOPD II have a shortened life-span because they are at increased risk for development of type 2 diabetes mellitus, obesity, and cerebrovascular accidents. MOPD II is not considered a syndrome of premature aging as these patients are not at risk for development of neoplasia nor do their chromosomal telomeres display an accelerated rate of shortening. Utilizing the families of patients with MOPD II born to consanguineous parents and genome wide linkage analysis, Rauch et al localized this disorder to chromosome 21q22.3—the site of PCNT2. After analysis of the 47 exons of PCNT2 in 25 unrelated patients with MOPD II, these investigators identified 29 distinct null mutations (12 stop and 17 frameshift) scattered through the gene. Interestingly, in patients with MOPD II, PCNT2 is transcribed (mRNA levels are normal or slightly decreased) but not translated (PCNT2 protein levels are absent or low), as its mRNA is subjected to nonsense-mediated mRNA decay directed by pretranslational mRNA surveillance mechanisms. Heterozygous (PCNT2+/-) parents synthesize less PCNT2 protein than normal subjects and are reported to have significantly short adult stature raising the possibility that variants of PCNT2 are involved in determination of stature in the normal population. Seckel syndrome is also a heterogeneous, autosomal recessive disorder that has been subclassified into types 1 through 4 depending on linkage to different chromosomal regions (3q22, 18p11, 14q, 21q22.3). It is characterized by symmetrical prenatal and postnatal growth retardation, microcephaly with developmental delay, and “bird-like” facial features (small head, large eyes, beak-like nose, micrognathia). The clinical characteristics of patients with Seckel syndrome type 4 (chromosome 21q22.3-qter; OMIM 611860) are similar to those of patients with other subtypes. Griffith et al, utilizing a genome wide association procedure in 2 consanguineous families with Seckel syndrome members, also localized the disorder to chromosome 21q22.3 and identified homozygous inactivating (nonsense, single base pair deletion or insertion) mutations in PCNT2 in affected patients. The reason that loss-of-function mutations in PCNT2 result in 2 clinically similar (microcephaly, facial features, growth retardation) but distinct (proportionate versus non-symmetrical short stature, reasonably normal mentation versus developmental delay) disorders of MOPD II or Seckel syndrome is uncertain. It has been suggested that in MOPD II, the PCNT2 mutations may adversely affect function of the centrosome, while in Seckel syndrome the mutations may impair mitotic progression.1 First Editor’s CommentSeckel syndrome type 1 has been ascribed to inactivating mutations in the DNA damage detection and repair ataxia-telangiectasia and Rad3-related gene (ATR; chromosome 3q22-24, OMIM 601205). Inactivation of PCNT2 adversely affects function of ATR protein-dependent effects on monitoring of the cell cycle; PCNT2 acts at a point downstream of ATR. Mutations in several genes that encode centrosomal and mitotic spindle-related proteins have been associated with isolated primary microcephaly with normal stature (CDK5RAP2, ASPM, MCPH6) and primary microcephaly with short stature (MCPH1). Homo floresiensis is species of hominids whose fossils have been found in Indonesia and who have several features in common with MOPD II including an adult height of 100 cm, small brain but normal intelligence, and skeletal anomalies raising speculation that they may have been humans with MOPD II or defects elsewhere in the DNA damage-repair pathways. The findings in patients with MOPD II and Seckel syndrome may be compared with those of Hutchinson-Gilford progeria,2,3 a syndrome of premature aging due to a monoallelic mutation in the gene (LMNA) encoding lamin A. Progeric subjects are characterized by postnatal growth retardation, small head circumference, abnormalities of the skin (altered pigmentation, sclerosis, alopecia), hypodontia, lipodystrophy, restricted joint mobility, cardiovascular abnormalities, and early death. Lamin A (chromosome 1q21.2, OMIM 150330) is an essential component of the protein network found within the nuclear membrane. Ninety percent of patients have a C-to-T substitution at nucleotide 1824 resulting in substitution at codon 608 of glycine GGC to glycine GGT. This nucleotide change activates a cryptic splice donor site that removes 150 nucleotides from transcribed LMNA mRNA. The translated protein retains farnesyl groups that link mutant and wt lamin A molecules and prevents their release from the inner nuclear membrane, thereby interfering with cell mitosis and gene expression. Experimentally, prevention of farnesyl attachment to mutated lamin A allows the protein to separate from the inner nuclear membrane. A drug that inhibits farnesyl transferase ameliorates a mouse model of progeria. An open-label trial of this agent is now underway in progeric patients. Allen W. Root, MD Second Editor’s CommentSeckel syndrome refers to a genetically heterogenous group of autosomal recessive conditions (SCKL1-4) characterized by severe pre- and postnatal growth deficiency and marked microcephaly. While all 4 conditions have been chromosomally mapped, the gene locus is known only for SCKL1; it encodes ATR, which functions to coordinate cellular responses to DNA damage. More specifically, ATR signaling responds to single-stranded DNA damage. Griffith and colleagues carried out an SNP-microarray genome-wide scan to detect regions of homozygosity on 2 consanguineous families with individuals clinically diagnosed with Seckel syndrome and showing evidence of defective ATR signaling. The scan identified a region on chromosome 21q22.3, which corresponds to the SCKL4 locus, that contained the gene encoding the centrosomal protein, PCNT. Pericentrin was considered a candidate because mutations in other centrisomal protein genes were known to cause primary microcephaly (Figure 2). Genomic sequencing revealed a homozygous nonsense mutation in exon 4 in affected members of one family and a homozygous single basepair deletion in the other; both were predicted to result in loss of function. A similar PCNT mutation was detected in a third patient with typical features of Seckel syndrome. Pericentrin localizes in cells to the pericentriolar material where it is believed to interact with several structural centrosomal proteins involved in the attachment of microtubules during mitotic spindle formation. It also appears to act as a scaffold to recruit signaling molecules, such as protein kinase A (PKA) to centrosomes. The authors carried out a number of experiments to document the absence of centrosomal pericentrin in patient cells. They also induced DNA damage with UV light and showed that ATR-dependent DNA damage response signaling that is normally activated during the cell cycle was defective similar to that observed in cells from patients with SCKL1 (Figure 3). This step is often referred to as G2-M checkpoint arrest, a process that prevents cells from entering into the M (mitotic) phase of the cell cycle with damaged DNA. The authors postulated that pericentrin deficiency interferes with growth through a general impairment in the progression of cells through mitosis. They also noted that identification of pericentrin mutations provides an interesting convergence between microcephaly genes implicated in ATR signaling and those involved in centrosomal function. It makes sense that the profound growth deficiency of Seckel syndrome is due to a disturbance in the machinery that directs cell division, but it would have been impossible to predict the specific defect without recent advances in genomic technology. William A. Horton, MD References - (linked to
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Volume 26 Number 1
September 2010
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ISSN 1932-9032
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