SHOX: A Geneticist’s View

Gudrun Rappold

Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany

Address correspondence to: Gundrun Rappold, M.D., University of Heidelberg, Institute of Human Genetics, Im Neuenheimer Feld 328, Heidelberg 69120, Germany. E-mail: . gundrun_rappold{at}med.uni-heidelberg.de

To the editor:

I would like to respond to the editorial of G. Rosenfeld, "A SHOX to the System" (1), and to the paper of Ross et al., "Phenotypes Associated with SHOX Deficiency" (2), in the recently published issue of the Journal of Clinical Endocrinology & Metabolism.

In the interesting paper of Ross et al. (2), 43 patients with Leri-Weill dyschondrosteosis (LWD) of 21 families were studied for defects in the SHOX gene and for their clinical phenotype. A mean height deficit of -2.2 SD (with a range from -4.6 to 0.6 SD) was found in LWD subjects with confirmed SHOX deficiency. SHOX represents a developmental gene (3), and genetic variability is a vital feature of all haploinsufficiency syndromes, yet it is surprising to see that 49% of the subjects with SHOX deficiency in this study had heights within the normal range. What may be the reason behind this? A closer look at the patient pool reveals that more than half are children below 18 yr of age. Furthermore, six of the individuals present a 46,X,der(X)t(X;Yq) translocation and have therefore likely translocated the Y-specific growth-controlling gene GCY onto the X chromosome (4). These patients are known to be taller because they have the additive statural effect of two SHOX copies and one GCY copy (5). Ross et al. (1) then conclude that the height deficit in LWD is approximately two thirds that of Turner syndrome. This value is based on their LWD patient population and is taken as an argument on the role and contribution of SHOX haploinsufficiency to Turner syndrome. Data from other groups, including our own, on 62 LWD subjects of 45 families (30 adults) have detected height deficits ranging from -6.4 to -0.6 SD with a mean SD of -3.2 in adults (unpublished data), which is very similar to the height deficit generally observed in Turner syndrome (-3.2 SD). Therefore, at this point, the results of Ross et al. (1) have to be interpreted with caution and are likely not conclusive with regard to the height effect of SHOX in Turner syndrome.

SHOX resides in the pseudoautosomal region (PAR1) at the tip of the short arms of the X and Y chromosomes. Genes located within PAR1 escape X-inactivation and are expressed from both the X and Y chromosomes. This implies that the SHOX gene cannot be considered X-linked in the classical sense because it has an identical active counterpart on the Y chromosome. Contrary to the opinion of Dr. Rosenfeld, therefore, male to male transmission can occur when the mutant SHOX gene on the Y chromosome of a father is transmitted to his son.

In addition, due to the exceptionally high recombination frequency in PAR1, interesting situations can arise when, for instance, the mutant SHOX gene on the father’s Y chromosome is transmitted to both his affected son (via the Y) and to his affected daughter (via the X), reflecting meiotic cross-over between the X and Y chromosomes (6). Unfortunately, this way of pseudoautosomal transmission does not provide any clue on the female to male preponderance in LWD patients. As Dr. Rosenfeld rightly pointed out in his editorial (1), there are still many exciting questions waiting to be answered.

Received December 21, 2001.

References

  1. Rosenfeld RG 2001 Editorial: A SHOX to the system. J Clin Endocrinol Metab 86:5672–5673[Free Full Text]
  2. Ross JL, Scott Jr C, Marttila P, Kowal K, Nass A, Papenhausen P, Abboudi J, Osterman L, Kushner H, Carter P, Ezaki M, Elder F, Wei F, Chen H, Zinn AR 2001 Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab 86:5674–5680[Abstract/Free Full Text]
  3. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, Muroya K, Binder G, Kirsch S, Winkelmann M, Nordsiek G, Heinrich U, Breuning MH, Ranke MB, Rosenthal A, Ogata T, Rappold GA 1997 Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16:54–63[Medline]
  4. Kirsch S, Weiss B, De Rosa M, Ogata T, Lombardi G, Rappold GA FISH deletion mapping defines a single location for the Y chromosome stature gene, GCY. J Med Genet 37:593–599
  5. Spranger S, Kirsch S, Mertz A, Schiebel K, Tariverdian G, Rappold GA 1997 Molecular studies of an X;Y translation chromosome in a woman with deletion of the pseudoautosomal region but normal height. Clin Genet 51:346–350[Medline]
  6. Shears DJ, Vassal HJ, Goodman FR, Palmer RW, Reardon W, Superti-Furga A, Scambler PJ, Winter RM 1998 Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschodrosteosis. Nat Genet 19:70–73[CrossRef][Medline]




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